bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2024‒03‒31
forty-one papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Elevation of hypothalamic ketone bodies induces a decrease in energy expenditures and an increase risk of metabolic disorder.
  2. In Vitro Astroglial Dysfunction Induced by Neurotoxins: Mimicking Astrocytic Metabolic Alterations of Alzheimer's Disease.
  3. Lactate Protects Microglia and Neurons from Oxygen-Glucose Deprivation/Reoxygenation.
  4. Navigating the metabolic maze: anomalies in fatty acid and cholesterol processes in Alzheimer's astrocytes.
  5. Does hyperphenylalaninemia induce brain glucose hypometabolism? Cerebral spinal fluid findings in treated adult phenylketonuric patients.
  6. Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies.
  7. The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner.
  8. Metabolite transport across central nervous system barriers.
  9. APOE and Alzheimer's disease: Pathologic clues from transgenic Drosophila melanogaster.
  10. Transcriptional and metabolic effects of aspartate-glutamate carrier isoform 1 (AGC1) downregulation in mouse oligodendrocyte precursor cells (OPCs).
  11. Myelin lesion in the aspartoacylase (Aspa) knockout rat, an animal model for Canavan disease.
  12. Palmitate Compromises C6 Astrocytic Cell Viability and Mitochondrial Function.
  13. TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.
  14. Oxygen-Glucose Deprivation Increases NR4A1 Expression and Promotes Its Extranuclear Translocation in Mouse Astrocytes.
  15. Ammoniagenic Action of Valproate without Signs of Hepatic Dysfunction in Rats: Possible Causes and Supporting Evidence.
  16. Therapeutic outcome of patients with Lennox-Gastaut syndrome with mitochondrial respiratory chain complex I deficiency.
  17. The Effects of the S1P Receptor Agonist Fingolimod (FTY720) on Central and Peripheral Myelin in Twitcher Mice.
  18. Senescence and aging differentially alter key metabolic pathways in murine brain microglia.
  19. Effects of Complete and Partial Loss of the 24S-Hydroxycholesterol-Generating Enzyme Cyp46a1 on Behavior and Hippocampal Transcription in Mouse.
  20. Dynamics of Mitochondrial Proteome and Acetylome in Glioblastoma Cells with Contrasting Metabolic Phenotypes.
  21. Lipid Rafts: The Maestros of Normal Brain Development.
  22. Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.
  23. Integrative Analysis of Cytokine and Lipidomics Datasets Following Mild Traumatic Brain Injury in Rats.
  24. Metabolomics of Multiple Sclerosis Lesions Demonstrates Lipid Changes Linked to Alterations in Transcriptomics-Based Cellular Profiles.
  25. Tracing the path of disruption: 13C isotope applications in traumatic brain injury-induced metabolic dysfunction.
  26. Complex I activity in hypoxia: implications for oncometabolism.
  27. The Relationship between Post-Traumatic Stress Disorder Due to Brain Injury and Glutamate Intake: A Systematic Review.
  28. Generation of novel anti-apoE monoclonal antibodies that selectively recognize apoE isoforms.
  29. Importance of the biochemical investigations for the functional characterization of a NPC1 variant identified by exome sequencing.
  30. Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.
  31. Bottlenecks in the Investigation of Retinal Sterol Homeostasis.
  32. Mitochondria-tau association promotes cognitive decline and hippocampal bioenergetic deficits during the aging.
  33. Long-term in vivo three-photon imaging reveals region-specific differences in healthy and regenerative oligodendrogenesis.
  34. BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria.
  35. Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8).
  36. Sulfide catabolism in hibernation and neuroprotection.
  37. Perinatal compromise affects development, form, and function of the hippocampus part one; clinical studies.
  38. The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier.
  39. Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
  40. Cortical lipid metabolic pathway alteration of early Alzheimer's disease and candidate drugs screen.
  41. [3H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain.
  1. Mol Metab. 2024 Mar 27. pii: S2212-8778(24)00057-7. [Epub ahead of print] 101926
    Elevation of hypothalamic ketone bodies induces a decrease in energy expenditures and an increase risk of metabolic disorder.
    Lionel Carneiro, Rocco Bernasconi, Adriano Bernini, Cendrine Repond, Luc Pellerin.
      OBJECTIVE: Ketone bodies (such as β-hydroxybutyrate or BHB) have been recently proposed as signals involved in brain regulation of energy homeostasis and obesity development. However, the precise role of ketone bodies sensing by the brain, and its impact on metabolic disorder development remains unclear. Nevertheless, partial deletion of the ubiquitous ketone bodies transporter MCT1 in mice (HE mice) results in diet-induced obesity resistance, while there is no alteration under normal chow diet. These results suggest that ketone bodies produced during the high fat diet would be important signals involved in obesity onset.METHODS: In the present study we used a specific BHB infusion of the hypothalamus and analyzed the energy homeostasis of WT or HE mice fed a normal chow diet.
    RESULTS: Our results indicate that high BHB levels sensed by the hypothalamus disrupt the brain regulation of energy homeostasis. This brain control dysregulation leads to peripheral alterations of energy expenditure mechanisms.
    CONCLUSION: Altogether, the changes induced by high ketone bodies levels sensed by the brain increase the risk of obesity onset in mice.
    Keywords:  ketone bodies; metabolism; neuroscience; obesity
    DOI:  https://doi.org/10.1016/j.molmet.2024.101926
  2. Metabolites. 2024 Mar 01. pii: 151. [Epub ahead of print]14(3):
    In Vitro Astroglial Dysfunction Induced by Neurotoxins: Mimicking Astrocytic Metabolic Alterations of Alzheimer's Disease.
    Jéssica Taday, Fernanda Telles Fróes, Marina Seady, Carlos Alberto Gonçalves, Marina Concli Leite.
      Astrocytes play fundamental roles in the maintenance of brain homeostasis. The dysfunction of these cells is widely associated with brain disorders, which are often characterized by variations in the astrocyte protein markers GFAP and S100B, in addition to alterations in some of its metabolic functions. To understand the role of astrocytes in neurodegeneration mechanisms, we induced some of these metabolic alterations, such as energy metabolism, using methylglyoxal (MG) or fluorocitrate (FC); and neuroinflammation, using lipopolysaccharide (LPS) and streptozotocin (STZ), which is used for inducing Alzheimer's disease (AD) in animal models. We showed that MG, LPS, STZ and FC similarly caused astrocyte dysfunction by increasing GFAP and reducing S100B secretion. In the context of AD, STZ caused an amyloid metabolism impairment verified by increases in Aβ1-40 peptide content and decreases in the amyloid degradation enzymes, IDE and NEP. Our data contribute to the understanding of the role of astrocytes in brain injury mechanisms and suggest that STZ is suitable for use in vitro models for studying the role of astrocytes in AD.
    Keywords:  Alzheimer’s disease; astrocytes; fluorocitrate; lipopolysaccharide; methylglyoxal; streptozotocin
    DOI:  https://doi.org/10.3390/metabo14030151
  3. Neurochem Res. 2024 Mar 29.
    Lactate Protects Microglia and Neurons from Oxygen-Glucose Deprivation/Reoxygenation.
    Isadora D'Ávila Tassinari, Fernanda da Silva Rodrigues, Craig Bertram, Daniella Arêas Mendes-da-Cruz, Renata Padilha Guedes, Ana Helena Paz, Victorio Bambini-Junior, Luciano Stürmer de Fraga.
      Lactate has received attention as a potential therapeutic intervention for brain diseases, particularly those including energy deficit, exacerbated inflammation, and disrupted redox status, such as cerebral ischemia. However, lactate roles in metabolic or signaling pathways in neural cells remain elusive in the hypoxic and ischemic contexts. Here, we tested the effects of lactate on the survival of a microglial (BV-2) and a neuronal (SH-SY5Y) cell lines during oxygen and glucose deprivation (OGD) or OGD followed by reoxygenation (OGD/R). Lactate signaling was studied by using 3,5-DHBA, an exogenous agonist of lactate receptor GPR81. Inhibition of lactate dehydrogenase (LDH) or monocarboxylate transporters (MCT), using oxamate or 4-CIN, respectively, was performed to evaluate the impact of lactate metabolization and transport on cell viability. The OGD lasted 6 h and the reoxygenation lasted 24 h following OGD (OGD/R). Cell viability, extracellular lactate concentrations, microglial intracellular pH and TNF-ɑ release, and neurite elongation were evaluated. Lactate or 3,5-DHBA treatment during OGD increased microglial survival during reoxygenation. Inhibition of lactate metabolism and transport impaired microglial and neuronal viability. OGD led to intracellular acidification in BV-2 cells, and reoxygenation increased the release of TNF-ɑ, which was reverted by lactate and 3,5-DHBA treatment. Our results suggest that lactate plays a dual role in OGD, acting as a metabolic and a signaling molecule in BV-2 and SH-SY5Y cells. Lactate metabolism and transport are vital for cell survival during OGD. Moreover, lactate treatment and GPR81 activation during OGD promote long-term adaptations that potentially protect cells against secondary cell death during reoxygenation.
    Keywords:  Lactate; Metabolism; Microglia; Neuron; Oxygen and glucose deprivation
    DOI:  https://doi.org/10.1007/s11064-024-04135-7
  4. Alzheimers Res Ther. 2024 Mar 23. 16(1): 63
    Navigating the metabolic maze: anomalies in fatty acid and cholesterol processes in Alzheimer's astrocytes.
    Xiaoyu Zhang, Chuanying Chen, Yi Liu.
      Alzheimer's disease (AD) is the most common cause of dementia, and its underlying mechanisms have been a subject of great interest. The mainstream theory of AD pathology suggests that the disease is primarily associated with tau protein and amyloid-beta (Aβ). However, an increasing body of research has revealed that abnormalities in lipid metabolism may be an important event throughout the pathophysiology of AD. Astrocytes, as important members of the lipid metabolism network in the brain, play a significant role in this event. The study of abnormal lipid metabolism in astrocytes provides a new perspective for understanding the pathogenesis of AD. This review focuses on the abnormal metabolism of fatty acids (FAs) and cholesterol in astrocytes in AD, and discusses it from three perspectives: lipid uptake, intracellular breakdown or synthesis metabolism, and efflux transport. We found that, despite the accumulation of their own fatty acids, astrocytes cannot efficiently uptake fatty acids from neurons, leading to fatty acid accumulation within neurons and resulting in lipotoxicity. In terms of cholesterol metabolism, astrocytes exhibit a decrease in endogenous synthesis due to the accumulation of exogenous cholesterol. Through a thorough investigation of these metabolic abnormalities, we can provide new insights for future therapeutic strategies by literature review to navigate this complex metabolic maze and bring hope to patients with Alzheimer's disease.
    Keywords:  Alzheimer’s disease; Astrocyte; Cholesterol; Fatty acid
    DOI:  https://doi.org/10.1186/s13195-024-01430-x
  5. Mol Genet Metab. 2024 Mar 23. pii: S1096-7192(24)00279-8. [Epub ahead of print]142(1): 108464
    Does hyperphenylalaninemia induce brain glucose hypometabolism? Cerebral spinal fluid findings in treated adult phenylketonuric patients.
    Friedrich Trefz, Georg Frauendienst-Egger, Gerald Dienel, Claire Cannet, Brigitte Schmidt-Mader, Dorothea Haas, Nenad Blau, Nastassja Himmelreich, Manfred Spraul, Peter Freisinger, Steven Dobrowolski, Daniela Berg, Andrea Pilotto.
      Despite numerous studies in human patients and animal models for phenylketonuria (PKU; OMIM#261600), the pathophysiology of PKU and the underlying causes of brain dysfunction and cognitive problems in PKU patients are not well understood. In this study, lumbar cerebral spinal fluid (CSF) was obtained immediately after blood sampling from early-treated adult PKU patients who had fasted overnight. Metabolite and amino acid concentrations in the CSF of PKU patients were compared with those of non-PKU controls. The CSF concentrations and CSF/plasma ratios for glucose and lactate were found to be below normal, similar to what has been reported for glucose transporter1 (GLUT1) deficiency patients who exhibit many of the same clinical symptoms as untreated PKU patients. CSF glucose and lactate levels were negatively correlated with CSF phenylalanine (Phe), while CSF glutamine and glutamate levels were positively correlated with CSF Phe levels. Plasma glucose levels were negatively correlated with plasma Phe concentrations in PKU subjects, which partly explains the reduced CSF glucose concentrations. Although brain glucose concentrations are unlikely to be low enough to impair brain glucose utilization, it is possible that the metabolism of Phe in the brain to produce phenyllactate, which can be transported across the blood-brain barrier to the blood, may consume glucose and/or lactate to generate the carbon backbone for glutamate. This glutamate is then converted to glutamine and carries the Phe-derived ammonia from the brain to the blood. While this mechanism remains to be tested, it may explain the correlations of CSF glutamine, glucose, and lactate concentrations with CSF Phe.
    Keywords:  Cerebral spinal fluid; Glucose; Lactate; Phenylalanine; Phenylketonuria; Plasma
    DOI:  https://doi.org/10.1016/j.ymgme.2024.108464
  6. J Neuroinflammation. 2024 Mar 27. 21(1): 78
    Changes in lipid metabolism track with the progression of neurofibrillary pathology in tauopathies.
    Dominika Olešová, Dana Dobešová, Petra Majerová, Radana Brumarová, Aleš Kvasnička, Štěpán Kouřil, Eva Stevens, Jozef Hanes, Ľubica Fialová, Alena Michalicová, Juraj Piešťanský, Jakub Šinský, Petr Kaňovský, David Friedecký, Andrej Kováč.
      BACKGROUND: Accumulation of tau leads to neuroinflammation and neuronal cell death in tauopathies, including Alzheimer's disease. As the disease progresses, there is a decline in brain energy metabolism. However, the role of tau protein in regulating lipid metabolism remains less characterized and poorly understood.METHODS: We used a transgenic rat model for tauopathy to reveal metabolic alterations induced by neurofibrillary pathology. Transgenic rats express a tau fragment truncated at the N- and C-terminals. For phenotypic profiling, we performed targeted metabolomic and lipidomic analysis of brain tissue, CSF, and plasma, based on the LC-MS platform. To monitor disease progression, we employed samples from transgenic and control rats aged 4, 6, 8, 10, 12, and 14 months. To study neuron-glia interplay in lipidome changes induced by pathological tau we used well well-established multicomponent cell model system. Univariate and multivariate statistical approaches were used for data evaluation.
    RESULTS: We showed that tau has an important role in the deregulation of lipid metabolism. In the lipidomic study, pathological tau was associated with higher production of lipids participating in protein fibrillization, membrane reorganization, and inflammation. Interestingly, significant changes have been found in the early stages of tauopathy before the formation of high-molecular-weight tau aggregates and neurofibrillary pathology. Increased secretion of pathological tau protein in vivo and in vitro induced upregulated production of phospholipids and sphingolipids and accumulation of lipid droplets in microglia. We also found that this process depended on the amount of extracellular tau. During the later stages of tauopathy, we found a connection between the transition of tau into an insoluble fraction and changes in brain metabolism.
    CONCLUSION: Our results revealed that lipid metabolism is significantly affected during different stages of tau pathology. Thus, our results demonstrate that the dysregulation of lipid composition by pathological tau disrupts the microenvironment, further contributing to the propagation of pathology.
    Keywords:  Lipid droplets; Lipidomics; Metabolomics; Microglia; Neurodegeneration; SHR24; Tau protein
    DOI:  https://doi.org/10.1186/s12974-024-03060-4
  7. Int J Mol Sci. 2024 Mar 20. pii: 3475. [Epub ahead of print]25(6):
    The Brain Metabolome Is Modified by Obesity in a Sex-Dependent Manner.
    Jennifer E Norman, Dragan Milenkovic, Saivageethi Nuthikattu, Amparo C Villablanca.
      Obesity is linked to cognitive decline and metabolic dysregulation in the brain, yet the role of sex is relatively unexplored. We sought to explore the effects of obesity and sex on the brain metabolome. In male and female ob/ob and wild-type mice, we assessed whole brain untargeted metabolomics by liquid chromatography-mass spectrometry, behavior by open field test, and cognitive function by Y-maze and Morris water maze. The metabolic profiles of ob/ob and wild-type mice differed in both sexes. There were more obesity-altered brain metabolites in males than females. Thirty-nine metabolites were unique to males, 15 were unique to females, and five were common to both sexes. Two of the common metabolites were involved in nicotinamide adenine dinucleotide homeostasis. A key feature of the metabolites identified in males was an increase in free fatty acids. In females, a unique feature was the presence of the neuro-modulatory metabolites 2-linoleoyl glycerol and taurine. The behavioral effects of obesity were only seen in females. These results demonstrate that most impacts of obesity on the brain metabolomic profile are sex-specific. Our work has implications for understanding the role of obesity in brain metabolism and the differential contribution of obesity to cognitive decline in males and females.
    Keywords:  brain; cognitive function; metabolomics; obesity; sex differences
    DOI:  https://doi.org/10.3390/ijms25063475
  8. J Cereb Blood Flow Metab. 2024 Mar 28. 271678X241241908
    Metabolite transport across central nervous system barriers.
    Gesa Carstens, Marcel M Verbeek, Ursula K Rohlwink, Anthony A Figaji, Lindsey Te Brake, Arjan van Laarhoven.
      Metabolomic analysis of cerebrospinal fluid (CSF) is used to improve diagnostics and pathophysiological understanding of neurological diseases. Alterations in CSF metabolite levels can partly be attributed to changes in brain metabolism, but relevant transport processes influencing CSF metabolite concentrations should be considered. The entry of molecules including metabolites into the central nervous system (CNS), is tightly controlled by the blood-brain, blood-CSF, and blood-spinal cord barriers, where aquaporins and membrane-bound carrier proteins regulate influx and efflux via passive and active transport processes. This report therefore provides reference for future CSF metabolomic work, by providing a detailed summary of the current knowledge on the location and function of the involved transporters and routing of metabolites from blood to CSF and from CSF to blood.
    Keywords:  Blood-brain barrier; blood-CSF barrier; brain metabolism; metabolomics; transport mechanisms
    DOI:  https://doi.org/10.1177/0271678X241241908
  9. Arch Gerontol Geriatr. 2024 Mar 20. pii: S0167-4943(24)00096-7. [Epub ahead of print]123 105420
    APOE and Alzheimer's disease: Pathologic clues from transgenic Drosophila melanogaster.
    Mohammad Haddadi, Mehrnaz Haghi, Niloofar Rezaei, Zahra Kiani, Taha Akkülah, Arzu Celik.
      Alzheimer's disease (AD) is one of the most common forms of neurodegenerative diseases. Apolipoprotein E4 (ApoE4) is the main genetic risk factor in the development of late-onset AD. However, the exact mechanism underlying ApoE4-mediated neurodegeneration remains unclear. We utilized Drosophila melanogaster to examine the neurotoxic effects of various human APOE isoforms when expressed specifically in glial and neural cells. We assessed impacts on mitochondrial dynamics, ER stress, lipid metabolism, and bio-metal ion concentrations in the central nervous system (CNS) of the transgenic flies. Dachshund antibody staining revealed a reduction in the number of Kenyon cells. Behavioral investigations including ethanol tolerance and learning and memory performance demonstrated neuronal dysfunction in APOE4-expressing larvae and adult flies. Transcription level of marf and drp-1 were found to be elevated in APOE4 flies, while atf4, atf6, and xbp-1 s showed down regulation. Enhanced concentrations of triglyceride and cholesterol in the CNS were observed in APOE4 transgenic flies, with especially pronounced effects upon glial-specific expression of the gene. Spectrophotometry of brain homogenate revealed enhanced Fe++ and Zn++ ion levels in conjunction with diminished Cu++ levels upon APOE4 expression. To explore therapeutic strategies, we subjected the flies to heat-shock treatment, aiming to activate heat-shock proteins (HSPs) and assess their potential to mitigate the neurotoxic effects of APOE isoforms. The results showed potential therapeutic benefits for APOE4-expressing flies, hinting at an ability to attenuate memory deterioration. Overall, our findings suggest that APOE4 can alter lipid metabolism, bio metal ion homeostasis, and disrupt the harmonious fission-fusion balance of neuronal and glial mitochondria, ultimately inducing ER stress. These alterations mirror the main clinical manifestations of AD in patients. Therefore, our work underscores the suitability of Drosophila as a fertile model for probing the pathological roles of APOE and furthering our understanding of diverse isoform-specific functions.
    Keywords:  APOE; Alzheimer's disease; Bio metals; Drosophila; ER stress; Lipid profile; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.archger.2024.105420
  10. Cell Mol Biol Lett. 2024 Mar 29. 29(1): 44
    Transcriptional and metabolic effects of aspartate-glutamate carrier isoform 1 (AGC1) downregulation in mouse oligodendrocyte precursor cells (OPCs).
    Nicola Balboni, Giorgia Babini, Eleonora Poeta, Michele Protti, Laura Mercolini, Maria Chiara Magnifico, Simona Nicole Barile, Francesca Massenzio, Antonella Pignataro, Federico M Giorgi, Francesco Massimo Lasorsa, Barbara Monti.
      Aspartate-glutamate carrier isoform 1 (AGC1) is a carrier responsible for the export of mitochondrial aspartate in exchange for cytosolic glutamate and is part of the malate-aspartate shuttle, essential for the balance of reducing equivalents in the cells. In the brain, mutations in SLC25A12 gene, encoding for AGC1, cause an ultra-rare genetic disease, reported as a neurodevelopmental encephalopathy, whose symptoms include global hypomyelination, arrested psychomotor development, hypotonia and seizures. Among the biological components most affected by AGC1 deficiency are oligodendrocytes, glial cells responsible for myelination processes, and their precursors [oligodendrocyte progenitor cells (OPCs)]. The AGC1 silencing in an in vitro model of OPCs was documented to cause defects of proliferation and differentiation, mediated by alterations of histone acetylation/deacetylation. Disrupting AGC1 activity could possibly reduce the availability of acetyl groups, leading to perturbation of many biological pathways, such as histone modifications and fatty acids formation for myelin production. Here, we explore the transcriptome of mouse OPCs partially silenced for AGC1, reporting results of canonical analyses (differential expression) and pathway enrichment analyses, which highlight a disruption in fatty acids synthesis from both a regulatory and enzymatic stand. We further investigate the cellular effects of AGC1 deficiency through the identification of most affected transcriptional networks and altered alternative splicing. Transcriptional data were integrated with differential metabolite abundance analysis, showing downregulation of several amino acids, including glutamine and aspartate. Taken together, our results provide a molecular foundation for the effects of AGC1 deficiency in OPCs, highlighting the molecular mechanisms affected and providing a list of actionable targets to mitigate the effects of this pathology.
    Keywords:  Mitochondria; Neurodevelopment; Oligodendrocytes; Omics analysis; SLC25A12/aralar1/AGC1 deficiency; White matter disorder
    DOI:  https://doi.org/10.1186/s11658-024-00563-z
  11. Exp Anim. 2024 Mar 28.
    Myelin lesion in the aspartoacylase (Aspa) knockout rat, an animal model for Canavan disease.
    Shuji Takeda, Rika Hoshiai, Miyuu Tanaka, Takeshi Izawa, Jyoji Yamate, Takashi Kuramoto, Mitsuru Kuwamura.
      Canavan disease (CD) is a fatal hereditary neurological disorder caused by a mutation in the aspartoacylase (ASPA) gene and characterized by neurological signs and vacuolation in the central nervous system (CNS). The mutation inhibits the hydrolysis of N-acetyl-aspartate (NAA) resulting in accumulation of NAA in the CNS. A new Aspa-knockout rat was generated by transcription activator-like effector nuclease (TALEN) technology. Herein we describe the pathological and morphometrical findings in the brain and spinal cords of Aspa-knockout rats. Although Aspa-knockout rats did not show any neurological signs, vacuolation with swollen axons, hypomyelination, and activated swollen astrocytes were observed mainly in the brainstem reticular formation, ascending and descending motor neuron pathway, and in the olfactory tract. Morphometrical analysis revealed no obvious change in the number of neurons. These changes in the CNS are similar to human CD, suggesting that this animal model would be useful for further study of treatment and understanding the pathophysiology of human CD.
    Keywords:  Canavan disease; aspartoacylase deficiency; central nervous system (CNS); knockout rat; vacuolation
    DOI:  https://doi.org/10.1538/expanim.23-0089
  12. Metabolites. 2024 Mar 12. pii: 161. [Epub ahead of print]14(3):
    Palmitate Compromises C6 Astrocytic Cell Viability and Mitochondrial Function.
    Luisa O Schmitt, Antonella Blanco, Sheila V Lima, Gianni Mancini, Natalia F Mendes, Alexandra Latini, Joana M Gaspar.
      Consumption of high-fat diets (HFD) is associated with brain alterations, including changes in feeding behavior, cognitive decline, and dementia. Astrocytes play a role in HFD-induced neuroinflammation and brain dysfunction; however, this process is not entirely understood. We hypothesized that exposure to saturated fatty acids can compromise astrocyte viability and mitochondrial function. The C6 (astrocytes) cell line was treated with palmitate or stearate (200 µM and 400 µM) for 6 h. Cell viability, morphology, inflammatory markers, and oxidative stress were evaluated. To assess mitochondrial function, various parameters were measured (membrane potential, mass, respiration, and complex activities). We observed that 6 h of treatment with 400 µM palmitate decreased cell viability, and treatment with 200 µM palmitate changed the astrocyte morphology. Palmitate increased inflammatory markers (TNF-α and IL6) but did not induce oxidative stress. Palmitate significantly decreased the mitochondrial membrane potential and mitochondrial mass. Complex I activity also decreased in palmitate-treated cells; however, no changes were observed in mitochondrial respiration. In conclusion, palmitate, a saturated fatty acid, induces inflammation and impairs mitochondrial function, leading to reduced astrocytic cell viability and changes in cellular morphology. Our study provides valuable insights into the potential mechanisms underlying the relationship between saturated fatty acids, astrocytes, and mitochondrial function in obesity-related brain dysfunction.
    Keywords:  astrocytes; inflammation; mitochondria; obesity; saturated fatty acids
    DOI:  https://doi.org/10.3390/metabo14030161
  13. Nat Neurosci. 2024 Mar 27.
    TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.
    Edward N Wilson, Congcong Wang, Michelle S Swarovski, Kristy A Zera, Hannah E Ennerfelt, Qian Wang, Aisling Chaney, Esha Gauba, Javier A Ramos Benitez, Yann Le Guen, Paras S Minhas, Maharshi Panchal, Yuting J Tan, Eran Blacher, Chinyere A Iweka, Haley Cropper, Poorva Jain, Qingkun Liu, Swapnil S Mehta, Abigail J Zuckerman, Matthew Xin, Jacob Umans, Jolie Huang, Aarooran S Durairaj, Geidy E Serrano, Thomas G Beach, Michael D Greicius, Michelle L James, Marion S Buckwalter, Melanie R McReynolds, Joshua D Rabinowitz, Katrin I Andreasson.
      Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-β42 oligomer-induced bioenergetic changes, suggesting that amyloid-β42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.
    DOI:  https://doi.org/10.1038/s41593-024-01610-w
  14. Brain Sci. 2024 Feb 29. pii: 244. [Epub ahead of print]14(3):
    Oxygen-Glucose Deprivation Increases NR4A1 Expression and Promotes Its Extranuclear Translocation in Mouse Astrocytes.
    Kengo Moriyama, Asako Horino, Kuniko Kohyama, Yasumasa Nishito, Tomohiro Morio, Hiroshi Sakuma.
      Hypoxic-ischemic brain injury induces metabolic dysfunction that ultimately leads to neuronal cell death. Astrocytes, a type of glial cell, play a key role in brain metabolism; however, their response to hypoxic-ischemic brain injury is not fully understood. Microglia were removed from murine primary mixed glial cultures to enrich astrocytes. Next, we explored genes whose expression is altered following oxygen-glucose deprivation using a microarray. Microarray analysis revealed that the expression of Nr4a1 and Nr4a3 is markedly increased in astrocyte-enriched cultures after 15 h of oxygen-glucose deprivation. The expression of both Nr4a1 and Nr4a3 was regulated by HIF-1α. At the protein level, NR4A1 was translocated from the nucleus to the cytoplasm following oxygen-glucose deprivation and co-localized with mitochondria in apoptotic cells; however, its localization was restored to the nucleus after reoxygenation. Oxygen-glucose deprivation causes an increase in NR4A1 mRNA in astrocytes as well as its nuclear to cytoplasmic transfer. Furthermore, reoxygenation enhances NR4A1 transcription and promotes its nuclear translocation.
    Keywords:  CDIM8; HIF-1α; NR4A1; NR4A3; mitochondria; oxygen–glucose deprivation; pexidartinib; reoxygenation
    DOI:  https://doi.org/10.3390/brainsci14030244
  15. Biomolecules. 2024 Mar 19. pii: 370. [Epub ahead of print]14(3):
    Ammoniagenic Action of Valproate without Signs of Hepatic Dysfunction in Rats: Possible Causes and Supporting Evidence.
    Gubidat Alilova, Lyudmila Tikhonova, Carmina Montoliu, Elena Kosenko.
      (1) Background: Valproic acid (VPA) is one of the frequently prescribed antiepileptic drugs and is generally considered well tolerated. However, VPA neurologic adverse effects in the absence of liver failure are fairly common, suggesting that in the mechanism for the development of VPA-induced encephalopathy, much more is involved than merely the exposure to hyperammonemia (HA) caused by liver insufficiency to perform detoxification. Taking into account the importance of the relationship between an impaired brain energy metabolism and elevated ammonia production, and based on the ability of VPA to interfere with neuronal oxidative pathways, the current study intended to investigate a potential regional ammoniagenic effect of VPA on rats' brains by determining activities of the enzymes responsible for ammonia production and neutralization. (2) Methods: Rats received a single intraperitoneal injection of VPA (50, 100, 250, 500 mg/kg). Plasma, the neocortex, the cerebellum, and the hippocampus were collected at 30 min after injection. The levels of ammonia, urea, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured in blood plasma. The activities of glutaminase and glutamate dehydrogenase (GDH) in mitochondria and the activities of AMP deaminase (AMPD), adenosine deaminase (ADA), and glutamine synthetase (GS) in cytosolic fractions isolated from rat brain regions were measured. Ammonia, ALT, and AST values were determined in the mitochondrial and cytosolic fractions. (3) Results: Multi-dose VPA treatment did not significantly affect the plasma levels of ammonia and urea or the ALT and AST liver enzymes. Significant dose-independent increases in the accumulation of ammonia were found only in the cytosol from the cerebellum and there was a strong correlation between the ammonia level and the ADA activity in this brain structure. A significant decrease in the AMPD and AST activities was observed, while the ALT activity was unaffected. Only the highest VPA dose (500 mg/kg) was associated with significantly less activity of GS compared to the control in all studied brain structures. In the mitochondria of all studied brain structures, VPA caused a dose-independent increases in ammonia levels, a high concentration of which was strongly and positively correlated with the increased GDH and ALT activity, while glutaminase activity remained unchanged, and AST activity significantly decreased compared to the control in all studied brain structures. (4) Conclusions: This study highlights the rat brain region-specific ammoniagenic effects of VPA, which may manifest themselves in the absence of hyperammonemia. Further research should analyze how the responsiveness of the different brain regions may vary in VPA-treated animals that exhibit compromised energy metabolism, leading to increased ammoniagenesis.
    Keywords:  ammoniagenesis in the rat brain; encephalopathy without liver failure; valproate
    DOI:  https://doi.org/10.3390/biom14030370
  16. Front Neurol. 2024 ;15 1305404
    Therapeutic outcome of patients with Lennox-Gastaut syndrome with mitochondrial respiratory chain complex I deficiency.
    Ji-Hoon Na, Young-Mock Lee.
      Background: Lennox-Gastaut syndrome (LGS), a severe developmental epileptic encephalopathy, has various underlying causes. Mitochondrial respiratory chain complex I (MRC I) deficiency is an important cause of metabolic disorders such as mitochondrial dysfunction that can compromise brain function, thereby causing intractable epilepsy, including LGS. Thus, it can be expected that the presence or absence of MRC I deficiency may affect the treatment outcome of patients with LGS.Objectives: In this retrospective study, we aimed to investigate differences in the epilepsy characteristics and treatment outcomes between patients with LGS with and without MRC I deficiency.
    Methods: We retrospectively reviewed the medical records of 92 patients with LGS. We divided 68 patients with LGS according to the presence (n = 30) or absence (n = 38) of MRC I deficiency and compared their epilepsy characteristics.
    Results: Generalized tonic and drop seizures were significantly worse in patients with LGS and MRC I deficiency than in those without MRC I deficiency group at the 1-year follow-up (p < 0.001) and final follow-up 1 (p < 0.001). Patients with LGS and MRC I deficiency had significantly fewer electroencephalogram (EEG) improvements compared to those without MRC I deficiency at the 1-year follow-up (p = 0.031). Additionally, in the final follow-up period, patients with LGS and MRC I deficiency had significantly less improvement in EEG findings compared to patients without MRC I deficiency (p < 0.001).
    Conclusion: The overall treatment prognosis-in terms of improvement in traumatic generalized tonic seizure, drop seizure, and EEG findings-is worse in patients with LGS and MRC I deficiency than that in patients with LGS but without MRC I deficiency. Additional and targeted treatment is required to treat LGS with MRC I deficiency.
    Keywords:  Lennox–Gastaut syndrome (LGS); epilepsy; mitochondrial disease; mitochondrial dysfunction; mitochondrial respiratory chain complex I deficiency
    DOI:  https://doi.org/10.3389/fneur.2024.1305404
  17. Biomedicines. 2024 Mar 06. pii: 594. [Epub ahead of print]12(3):
    The Effects of the S1P Receptor Agonist Fingolimod (FTY720) on Central and Peripheral Myelin in Twitcher Mice.
    Sibylle Béchet, Kumlesh K Dev.
      Krabbe's disease (KD) is caused by mutations in the lysosomal enzyme galactocerebrosidase and is associated with psychosine toxicity. The sphingosine 1-phosphate receptor (S1PR) agonist fingolimod (FTY720) attenuates psychosine-induced cell death of human astrocytes, demyelination in cerebellar slices, as well as demyelination in the central nervous system of twitcher mice. Psychosine also accumulates in the peripheral nervous system in twitcher mice; however, effects of fingolimod on this peripheral myelin have not been examined. The aim of this study was to investigate the effects of fingolimod administration on peripheral and central markers of myelination. Here, we report that fingolimod administration (1 mg/kg/day) from postnatal day 5 (PND) onwards did not alter peripheral demyelination in the sciatic nerve of twitcher mice, despite significantly reducing myelin debris, glial reactivity, and neuronal damage in the cerebellum. We also find fingolimod administration improves twitching and mobility scores in twitcher mice. Importantly, we find that fingolimod significantly increases the lifespan of twitcher mice by approximately 5 days. These findings suggest differential effects of fingolimod on peripheral and central neuropathy in twitcher mice, which may explain its modest efficacy on behavior and lifespan.
    Keywords:  FTY720; Krabbe’s disease; S1P receptors; globoid cell leukodystrophy; myelination
    DOI:  https://doi.org/10.3390/biomedicines12030594
  18. Neurosci Lett. 2024 Mar 26. pii: S0304-3940(24)00128-9. [Epub ahead of print] 137751
    Senescence and aging differentially alter key metabolic pathways in murine brain microglia.
    Milan R Stojiljkovic, Christian Schmeer, Otto W Witte.
      Microglia, the resident immune cells of the central nervous system, are critically involved in maintaining brain homeostasis. With age, microglia display morphological and functional alterations that have been associated with cognitive decline and neurodegeneration. Although microglia seem to participate in an increasing number of biological processes which require a high energy demand, little is known about their metabolic regulation under physiological and pathophysiological conditions and during aging/senescence. Here, we determined mRNA expression levels of critical rate limiting enzymes in several key metabolic pathways including glycolysis, pentose phosphate pathway, fatty acid oxidation and synthesis in association with oxidative phosphorylation in microglia, both under aging and senescent conditions. We found strong evidence for different metabolic changes occuring in senescent vs. aged microglia cells. While senescent microglia display a hypermetabolic state as indicated by increased expression of key enzymes involved in glycolysis and pentose phosphate pathway, aging microglia are rather in a state of hypometabolism. Our findings indicate that studies involving aging and senescent microglia require a clear differentiation between these microglial states due to profound metabolic differences observed here. Understanding metabolic changes in senescent and aged microglia may lead to novel strategies to decrease over-activation of these cells due to aging, which is associated to the process of inflamm-aging and neurodegeneration.
    Keywords:  Aging; Immune system; Metabolism; Microglia; Senescence
    DOI:  https://doi.org/10.1016/j.neulet.2024.137751
  19. Biomolecules. 2024 Feb 21. pii: 254. [Epub ahead of print]14(3):
    Effects of Complete and Partial Loss of the 24S-Hydroxycholesterol-Generating Enzyme Cyp46a1 on Behavior and Hippocampal Transcription in Mouse.
    Hong-Jin Shu, Luke H Ziolkowski, Sofia V Salvatore, Ann M Benz, David F Wozniak, Carla M Yuede, Steven M Paul, Charles F Zorumski, Steven Mennerick.
      Brain cholesterol metabolic products include neurosteroids and oxysterols, which play important roles in cellular physiology. In neurons, the cholesterol oxidation product, 24S-hydroxycholesterol (24S-HC), is a regulator of signaling and transcription. Here, we examined the behavioral effects of 24S-HC loss, using global and cell-selective genetic deletion of the synthetic enzyme CYP46A1. Mice that are globally deficient in CYP46A1 exhibited hypoactivity at young ages and unexpected increases in conditioned fear memory. Despite strong reductions in hippocampal 24S-HC in mice with selective loss of CYP46A1 in VGLUT1-positive cells, behavioral effects were not recapitulated in these conditional knockout mice. Global knockout produced strong, developmentally dependent transcriptional effects on select cholesterol metabolism genes. These included paradoxical changes in Liver X Receptor targets. Again, conditional knockout was insufficient to recapitulate most changes. Overall, our results highlight the complex effects of 24S-HC in an in vivo setting that are not fully predicted by known mechanisms. The results also demonstrate that the complete inhibition of enzymatic activity may be needed for a detectable, therapeutically relevant impact on gene expression and behavior.
    Keywords:  24S-hydroxycholesterol; hippocampus; learning; liver X receptor; oxysterol
    DOI:  https://doi.org/10.3390/biom14030254
  20. Int J Mol Sci. 2024 Mar 19. pii: 3450. [Epub ahead of print]25(6):
    Dynamics of Mitochondrial Proteome and Acetylome in Glioblastoma Cells with Contrasting Metabolic Phenotypes.
    Diana Lashidua Fernández-Coto, Jeovanis Gil, Guadalupe Ayala, Sergio Encarnación-Guevara.
      Glioblastoma, a type of cancer affecting the central nervous system, is characterized by its poor prognosis and the dynamic alteration of its metabolic phenotype to fuel development and progression. Critical to cellular metabolism, mitochondria play a pivotal role, where the acetylation of lysine residues on mitochondrial enzymes emerges as a crucial regulatory mechanism of protein function. This post-translational modification, which negatively impacts the mitochondrial proteome's functionality, is modulated by the enzyme sirtuin 3 (SIRT3). Aiming to elucidate the regulatory role of SIRT3 in mitochondrial metabolism within glioblastoma, we employed high-resolution mass spectrometry to analyze the proteome and acetylome of two glioblastoma cell lines, each exhibiting distinct metabolic behaviors, following the chemical inhibition of SIRT3. Our findings reveal that the protein synthesis machinery, regulated by lysine acetylation, significantly influences the metabolic phenotype of these cells. Moreover, we have shed light on potential novel SIRT3 targets, thereby unveiling new avenues for future investigations. This research highlights the critical function of SIRT3 in mitochondrial metabolism and its broader implications for cellular energetics. It also provides a comparative analysis of the proteome and acetylome across glioblastoma cell lines with opposing metabolic phenotypes.
    Keywords:  SIRT3; glioblastoma; lysine acetylation; metabolism; mitochondria
    DOI:  https://doi.org/10.3390/ijms25063450
  21. Biomolecules. 2024 Mar 18. pii: 362. [Epub ahead of print]14(3):
    Lipid Rafts: The Maestros of Normal Brain Development.
    Barbara Viljetić, Senka Blažetić, Irena Labak, Vedrana Ivić, Milorad Zjalić, Marija Heffer, Marta Balog.
      Lipid rafts, specialised microdomains within cell membranes, play a central role in orchestrating various aspects of neurodevelopment, ranging from neural differentiation to the formation of functional neuronal networks. This review focuses on the multifaceted involvement of lipid rafts in key neurodevelopmental processes, including neural differentiation, synaptogenesis and myelination. Through the spatial organisation of signalling components, lipid rafts facilitate precise signalling events that determine neural fate during embryonic development and in adulthood. The evolutionary conservation of lipid rafts underscores their fundamental importance for the structural and functional complexity of the nervous system in all species. Furthermore, there is increasing evidence that environmental factors can modulate the composition and function of lipid rafts and influence neurodevelopmental processes. Understanding the intricate interplay between lipid rafts and neurodevelopment not only sheds light on the fundamental mechanisms governing brain development but also has implications for therapeutic strategies aimed at cultivating neuronal networks and addressing neurodevelopmental disorders.
    Keywords:  environmental factor; evolution; lipid rafts; myelination; neurodevelopment; synaptogenesis
    DOI:  https://doi.org/10.3390/biom14030362
  22. Curr Issues Mol Biol. 2024 Mar 02. 46(3): 1987-2026
    Mitochondrial Dysfunction: A Key Player in Brain Aging and Diseases.
    Sydney Bartman, Giuseppe Coppotelli, Jaime M Ross.
      Mitochondria are thought to have become incorporated within the eukaryotic cell approximately 2 billion years ago and play a role in a variety of cellular processes, such as energy production, calcium buffering and homeostasis, steroid synthesis, cell growth, and apoptosis, as well as inflammation and ROS production. Considering that mitochondria are involved in a multitude of cellular processes, mitochondrial dysfunction has been shown to play a role within several age-related diseases, including cancers, diabetes (type 2), and neurodegenerative diseases, although the underlying mechanisms are not entirely understood. The significant increase in lifespan and increased incidence of age-related diseases over recent decades has confirmed the necessity to understand the mechanisms by which mitochondrial dysfunction impacts the process of aging and age-related diseases. In this review, we will offer a brief overview of mitochondria, along with structure and function of this important organelle. We will then discuss the cause and consequence of mitochondrial dysfunction in the aging process, with a particular focus on its role in inflammation, cognitive decline, and neurodegenerative diseases, such as Huntington's disease, Parkinson's disease, and Alzheimer's disease. We will offer insight into therapies and interventions currently used to preserve or restore mitochondrial functioning during aging and neurodegeneration.
    Keywords:  aging; mitochondria; mitochondrial dysfunction; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/cimb46030130
  23. Metabolites. 2024 Feb 21. pii: 133. [Epub ahead of print]14(3):
    Integrative Analysis of Cytokine and Lipidomics Datasets Following Mild Traumatic Brain Injury in Rats.
    Alexis N Pulliam, Alyssa F Pybus, David A Gaul, Samuel G Moore, Levi B Wood, Facundo M Fernández, Michelle C LaPlaca.
      Traumatic brain injury (TBI) is a significant source of disability in the United States and around the world and may lead to long-lasting cognitive deficits and a decreased quality of life for patients across injury severities. Following the primary injury phase, TBI is characterized by complex secondary cascades that involve altered homeostasis and metabolism, faulty signaling, neuroinflammation, and lipid dysfunction. The objectives of the present study were to (1) assess potential correlations between lipidome and cytokine changes after closed-head mild TBI (mTBI), and (2) examine the reproducibility of our acute lipidomic profiles following TBI. Cortices from 54 Sprague Dawley male and female rats were analyzed by ultra-high-performance liquid chromatography mass spectrometry (LC-MS) in both positive and negative ionization modes and multiplex cytokine analysis after single (smTBI) or repetitive (rmTBI) closed-head impacts, or sham conditions. Tissue age was a variable, given that two cohorts (n = 26 and n = 28) were initially run a year-and-a-half apart, creating inter-batch variations. We annotated the lipidome datasets using an in-house data dictionary based on exact masses of precursor and fragment ions and removed features with statistically significant differences between sham control batches. Our results indicate that lipids with high-fold change between injury groups moderately correlate with the cytokines eotaxin, IP-10, and TNF-α. Additionally, we show a significant decrease in the pro-inflammatory markers IL-1β and IP-10, TNF-α, and RANTES in the rmTBI samples relative to the sham control. We discuss the major challenges in correlating high dimensional lipidomic data with functional cytokine profiles and the implications for understanding the biological significance of two related but disparate analysis modes in the study of TBI, an inherently heterogeneous neurological disorder.
    Keywords:  cytokines; lipidomics; multi-omics; neuroinflammation; traumatic brain injury
    DOI:  https://doi.org/10.3390/metabo14030133
  24. Neurol Neuroimmunol Neuroinflamm. 2024 May;11(3): e200219
    Metabolomics of Multiple Sclerosis Lesions Demonstrates Lipid Changes Linked to Alterations in Transcriptomics-Based Cellular Profiles.
    Dimitrios C Ladakis, Edoardo Pedrini, Maria I Reyes-Mantilla, Muraleetharan Sanjayan, Matthew D Smith, Kathryn C Fitzgerald, Carlos A Pardo, Daniel S Reich, Martina Absinta, Pavan Bhargava.
      BACKGROUND AND OBJECTIVES: People with multiple sclerosis (MS) have a dysregulated circulating metabolome, but the metabolome of MS brain lesions has not been studied. The aims of this study were to identify differences in the brain tissue metabolome in MS compared with controls and to assess its association with the cellular profile of corresponding tissue.METHODS: MS tissues included samples from the edge and core of chronic active or inactive lesions and periplaque white matter (WM). Control specimens were obtained from normal WM. Metabolomic analysis was performed using mass-spectrometry coupled with liquid/gas chromatography and subsequently integrated with single-nucleus RNA-sequencing data by correlating metabolite abundances with relative cell counts, as well as individual genes using Multiomics Factor Analysis (MOFA).
    RESULTS: Seventeen samples from 5 people with secondary progressive MS and 8 samples from 6 controls underwent metabolomic profiling identifying 783 metabolites. MS lesions had higher levels of sphingosines (false discovery rate-adjusted p-value[q] = 2.88E-05) and sphingomyelins and ceramides (q = 2.15E-07), but lower nucleotide (q = 0.05), energy (q = 0.001), lysophospholipid (q = 1.86E-07), and monoacylglycerol (q = 0.04) metabolite levels compared with control WM. Periplaque WM had elevated sphingomyelins and ceramides (q = 0.05) and decreased energy metabolites (q = 0.01) and lysophospholipids (q = 0.05) compared with control WM. Sphingolipids and membrane lipid metabolites were positively correlated with astrocyte and immune cell abundances and negatively correlated with oligodendrocytes. On the other hand, long-chain fatty acid, endocannabinoid, and monoacylglycerol pathways were negatively correlated with astrocyte and immune cell populations and positively correlated with oligodendrocytes. MOFA demonstrated associations between differentially expressed metabolites and genes involved in myelination and lipid biosynthesis.
    DISCUSSION: MS lesions and perilesional WM demonstrated a significantly altered metabolome compared with control WM. Many of the altered metabolites were associated with altered cellular composition and gene expression, indicating an important role of lipid metabolism in chronic neuroinflammation in MS.
    DOI:  https://doi.org/10.1212/NXI.0000000000200219
  25. CNS Neurosci Ther. 2024 Mar;30(3): e14693
    Tracing the path of disruption: 13C isotope applications in traumatic brain injury-induced metabolic dysfunction.
    Charles J Peper, Mitchell D Kilgore, Yinghua Jiang, Yuwen Xiu, Winna Xia, Yingjie Wang, Mengxuan Shi, Di Zhou, Aaron S Dumont, Xiaoying Wang, Ning Liu.
      Cerebral metabolic dysfunction is a critical pathological hallmark observed in the aftermath of traumatic brain injury (TBI), as extensively documented in clinical investigations and experimental models. An in-depth understanding of the bioenergetic disturbances that occur following TBI promises to reveal novel therapeutic targets, paving the way for the timely development of interventions to improve patient outcomes. The 13C isotope tracing technique represents a robust methodological advance, harnessing biochemical quantification to delineate the metabolic trajectories of isotopically labeled substrates. This nuanced approach enables real-time mapping of metabolic fluxes, providing a window into the cellular energetic state and elucidating the perturbations in key metabolic circuits. By applying this sophisticated tool, researchers can dissect the complexities of bioenergetic networks within the central nervous system, offering insights into the metabolic derangements specific to TBI pathology. Embraced by both animal studies and clinical research, 13C isotope tracing has bolstered our understanding of TBI-induced metabolic dysregulation. This review synthesizes current applications of isotope tracing and its transformative potential in evaluating and addressing the metabolic sequelae of TBI.
    Keywords:  13C isotope; bioenergetics; metabolism; traumatic brain injury
    DOI:  https://doi.org/10.1111/cns.14693
  26. Biochem Soc Trans. 2024 Mar 25. pii: BST20230189. [Epub ahead of print]
    Complex I activity in hypoxia: implications for oncometabolism.
    Christos Chinopoulos.
      Certain cancer cells within solid tumors experience hypoxia, rendering them incapable of oxidative phosphorylation (OXPHOS). Despite this oxygen deficiency, these cells exhibit biochemical pathway activity that relies on NAD+. This mini-review scrutinizes the persistent, residual Complex I activity that oxidizes NADH in the absence of oxygen as the electron acceptor. The resulting NAD+ assumes a pivotal role in fueling the α-ketoglutarate dehydrogenase complex, a critical component in the oxidative decarboxylation branch of glutaminolysis - a hallmark oncometabolic pathway. The proposition is that through glutamine catabolism, high-energy phosphate intermediates are produced via substrate-level phosphorylation in the mitochondrial matrix substantiated by succinyl-CoA ligase, partially compensating for an OXPHOS deficiency. These insights provide a rationale for exploring Complex I inhibitors in cancer treatment, even when OXPHOS functionality is already compromised.
    Keywords:  OXPHOS; cancer; hypoxia; mitochondria; mtSLP
    DOI:  https://doi.org/10.1042/BST20230189
  27. Nutrients. 2024 Mar 21. pii: 901. [Epub ahead of print]16(6):
    The Relationship between Post-Traumatic Stress Disorder Due to Brain Injury and Glutamate Intake: A Systematic Review.
    Benjamin F Gruenbaum, Alexander Zlotnik, Anna Oleshko, Frederic Matalon, Honore N Shiyntum, Amit Frenkel, Matthew Boyko.
      There is a growing body of evidence that suggests a connection between traumatic brain injury (TBI) and subsequent post-traumatic stress disorder (PTSD). While the exact mechanism is unknown, we hypothesize that chronic glutamate neurotoxicity may play a role. The consumption of dietary glutamate is a modifiable factor influencing glutamate levels in the blood and, therefore, in the brain. In this systematic review, we explored the relationship between dietary glutamate and the development of post-TBI PTSD. Of the 1748 articles identified, 44 met the inclusion criteria for analysis in this review. We observed that individuals from countries with diets traditionally high in glutamate had greater odds of developing PTSD after TBI (odds ratio = 15.2, 95% confidence interval 11.69 to 19.76, p < 0.01). These findings may support the hypothesis that chronically elevated blood glutamate concentrations caused by high dietary intake invoke neurodegeneration processes that could ultimately result in PTSD. Further studies will clarify whether lowering glutamate via diet would be an effective strategy in preventing or treating post-TBI PTSD.
    Keywords:  blood–brain barrier; diet; glutamate; post-traumatic stress disorder; traumatic brain injury
    DOI:  https://doi.org/10.3390/nu16060901
  28. FEBS Lett. 2024 Mar 26.
    Generation of novel anti-apoE monoclonal antibodies that selectively recognize apoE isoforms.
    Takashi Ohgita, Koto Sakai, Nodoka Fukui, Norihiro Namba, Miyu Nakano, Yuki Kiguchi, Izumi Morita, Hiroyuki Oyama, Kouya Yamaki, Kohjiro Nagao, Norihiro Kobayashi, Hiroyuki Saito.
      Apolipoprotein E (apoE) is a regulator of lipid metabolism, cholesterol transport, and the clearance and aggregation of amyloid β in the brain. The three human apoE isoforms apoE2, apoE3, and apoE4 only differ in one or two residues. Nevertheless, the functions highly depend on the isoform types and lipidated states. Here, we generated novel anti-apoE monoclonal antibodies (mAbs) and obtained an apoE4-selective mAb whose epitope is within residues 110-117. ELISA and bio-layer interferometry measurements demonstrated that the dissociation constants of mAbs are within the nanomolar range. Using the generated antibodies, we successfully constructed sandwich ELISA systems, which can detect all apoE isoforms or selectively detect apoE4. These results suggest the usability of the generated anti-apoE mAbs for selective detection of apoE isoforms.
    Keywords:  apoE isoform; monoclonal antibody; sandwich ELISA
    DOI:  https://doi.org/10.1002/1873-3468.14858
  29. Am J Med Genet A. 2024 Mar 29. e63595
    Importance of the biochemical investigations for the functional characterization of a NPC1 variant identified by exome sequencing.
    Nihal Almenabawy, Clara Hung, Iveta Sosova, Saadet Mercimek-Andrews.
      Niemann-Pick disease type C (NPC) is one of the lysosomal storage disorders. It is caused by biallelic pathogenic variants in NPC1 or NPC2, which results in a defective cholesterol trafficking inside the late endosome and lysosome. There is a high clinical variability in the age of presentation and the phenotype of this disorder making the diagnosis challenging. Here, we report a patient with an infantile onset global developmental delay, microcephaly and dysmorphic features, homozygous for c.3560C>T (p.A1187V) variant in NPC1. His plasma oxysterol levels were normal on two occasions. His lyso-sphingomyelin-509 (lyso-SM 509) and urinary bile acid levels were normal. Based on the phenotype and biochemical features, the diagnosis of NPC was excluded in this patient. We emphasize the importance of functional characterization in the classification of novel variants to prevent a misdiagnosis. Matching the phenotype and biochemical evidence with the molecular genomic tests is crucial for the confirmation of genetic diagnoses.
    Keywords:  Niemann–Pick type C; biomarker; developmental delay; exome sequencing; oxysterol
    DOI:  https://doi.org/10.1002/ajmg.a.63595
  30. Science. 2024 Mar 29. 383(6690): 1484-1492
    Pyrimidines maintain mitochondrial pyruvate oxidation to support de novo lipogenesis.
    Umakant Sahu, Elodie Villa, Colleen R Reczek, Zibo Zhao, Brendan P O'Hara, Michael D Torno, Rohan Mishra, William D Shannon, John M Asara, Peng Gao, Ali Shilatifard, Navdeep S Chandel, Issam Ben-Sahra.
      Cellular purines, particularly adenosine 5'-triphosphate (ATP), fuel many metabolic reactions, but less is known about the direct effects of pyrimidines on cellular metabolism. We found that pyrimidines, but not purines, maintain pyruvate oxidation and the tricarboxylic citric acid (TCA) cycle by regulating pyruvate dehydrogenase (PDH) activity. PDH activity requires sufficient substrates and cofactors, including thiamine pyrophosphate (TPP). Depletion of cellular pyrimidines decreased TPP synthesis, a reaction carried out by TPP kinase 1 (TPK1), which reportedly uses ATP to phosphorylate thiamine (vitamin B1). We found that uridine 5'-triphosphate (UTP) acts as the preferred substrate for TPK1, enabling cellular TPP synthesis, PDH activity, TCA-cycle activity, lipogenesis, and adipocyte differentiation. Thus, UTP is required for vitamin B1 utilization to maintain pyruvate oxidation and lipogenesis.
    DOI:  https://doi.org/10.1126/science.adh2771
  31. Biomolecules. 2024 Mar 12. pii: 341. [Epub ahead of print]14(3):
    Bottlenecks in the Investigation of Retinal Sterol Homeostasis.
    Sriganesh Ramachandra Rao, Steven J Fliesler.
      Sterol homeostasis in mammalian cells and tissues involves balancing three fundamental processes: de novo sterol biosynthesis; sterol import (e.g., from blood-borne lipoproteins); and sterol export. In complex tissues, composed of multiple different cell types (such as the retina), import and export also may involve intratissue, intercellular sterol exchange. Disruption of any of these processes can result in pathologies that impact the normal structure and function of the retina. Here, we provide a brief overview of what is known currently about sterol homeostasis in the vertebrate retina and offer a proposed path for future experimental work to further our understanding of these processes, with relevance to the development of novel therapeutic interventions for human diseases involving defective sterol homeostasis.
    Keywords:  cholesterol; homeostasis; lipid; lipoprotein; retina; retinal degeneration; sterol
    DOI:  https://doi.org/10.3390/biom14030341
  32. Free Radic Biol Med. 2024 Mar 27. pii: S0891-5849(24)00142-4. [Epub ahead of print]
    Mitochondria-tau association promotes cognitive decline and hippocampal bioenergetic deficits during the aging.
    Margrethe A Olesen, Eugenia Pradenas, Francisca Villavicencio-Tejo, George A Porter, Gail V W Johnson, Rodrigo A Quintanilla.
      Current studies indicate that pathological modifications of tau are associated with mitochondrial dysfunction, synaptic failure, and cognitive decline in neurological disorders and aging. We previously showed that caspase-3 cleaved tau, a relevant tau form in Alzheimer's disease (AD), affects mitochondrial bioenergetics, dynamics and synaptic plasticity by the opening of mitochondrial permeability transition pore (mPTP). Also, genetic ablation of tau promotes mitochondrial function boost and increased cognitive capacities in aging mice. However, the mechanisms and relevance of these alterations for the cognitive and mitochondrial abnormalities during aging, which is the primary risk factor for AD, has not been explored. Therefore, in this study we used aging C57BL/6 mice (2-15 and 28-month-old) to evaluate hippocampus-dependent cognitive performance and mitochondrial function. Behavioral tests revealed that aged mice (15 and 28-month-old) showed a reduced cognitive performance compared to young mice (2 month). Concomitantly, isolated hippocampal mitochondria of aged mice showed a significant decrease in bioenergetic-related functions including increases in reactive oxygen species (ROS), mitochondrial depolarization, ATP decreases, and calcium handling defects. Importantly, full-length and caspase-3 cleaved tau were preferentially present in mitochondrial fractions of 15 and 28-month-old mice. Also, aged mice (15 and 28-month-old) showed an increase in cyclophilin D (CypD), the principal regulator of mPTP opening, and a decrease in Opa-1 mitochondrial localization, indicating a possible defect in mitochondrial dynamics. Importantly, we corroborated these findings in immortalized cortical neurons expressing mitochondrial targeted full-length (GFP-T4-OMP25) and caspase-3 cleaved tau (GFP-T4C3-OMP25) which resulted in increased ROS levels and mitochondrial fragmentation, along with a decrease in Opa-1 protein expression. These results suggest that tau associates with mitochondria and this binding increases during aging. This connection may contribute to defects in mitochondrial bioenergetics and dynamics which later may conduce to cognitive decline present during aging.
    Keywords:  Aging; Mitochondria; Mitochondrial permeability transition pore (mPTP); Synaptic loss; Tau
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.03.017
  33. Nat Neurosci. 2024 Mar 27.
    Long-term in vivo three-photon imaging reveals region-specific differences in healthy and regenerative oligodendrogenesis.
    Michael A Thornton, Gregory L Futia, Michael E Stockton, Samuel A Budoff, Alexandra N Ramirez, Baris Ozbay, Omer Tzang, Karl Kilborn, Alon Poleg-Polsky, Diego Restrepo, Emily A Gibson, Ethan G Hughes.
      The generation of new myelin-forming oligodendrocytes in the adult central nervous system is critical for cognitive function and regeneration following injury. Oligodendrogenesis varies between gray and white matter regions, suggesting that local cues drive regional differences in myelination and the capacity for regeneration. However, the layer- and region-specific regulation of oligodendrocyte populations is unclear due to the inability to monitor deep brain structures in vivo. Here we harnessed the superior imaging depth of three-photon microscopy to permit long-term, longitudinal in vivo three-photon imaging of the entire cortical column and subcortical white matter in adult mice. We find that cortical oligodendrocyte populations expand at a higher rate in the adult brain than those of the white matter. Following demyelination, oligodendrocyte replacement is enhanced in the white matter, while the deep cortical layers show deficits in regenerative oligodendrogenesis and the restoration of transcriptional heterogeneity. Together, our findings demonstrate that regional microenvironments regulate oligodendrocyte population dynamics and heterogeneity in the healthy and diseased brain.
    DOI:  https://doi.org/10.1038/s41593-024-01613-7
  34. Cancer Metab. 2024 Mar 26. 12(1): 10
    BCAA metabolism in pancreatic cancer affects lipid balance by regulating fatty acid import into mitochondria.
    Klára Gotvaldová, Jitka Špačková, Jiří Novotný, Kamila Baslarová, Petr Ježek, Lenka Rossmeislová, Jan Gojda, Katarína Smolková.
      BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been associated with the host dysmetabolism of branched-chain amino acids (BCAAs), however, the implications for the role of BCAA metabolism in PDAC development or progression are not clear. The mitochondrial catabolism of valine, leucine, and isoleucine is a multistep process leading to the production of short-chain R-CoA species. They can be subsequently exported from mitochondria as short-chain carnitines (SC-CARs), utilized in anabolic pathways, or released from the cells.METHODS: We examined the specificities of BCAA catabolism and cellular adaptation strategies to BCAA starvation in PDAC cells in vitro. We used metabolomics and lipidomics to quantify major metabolic changes in response to BCAA withdrawal. Using confocal microscopy and flow cytometry we quantified the fluorescence of BODIPY probe and the level of lipid droplets (LDs). We used BODIPY-conjugated palmitate to evaluate transport of fatty acids (FAs) into mitochondria. Also, we have developed a protocol for quantification of SC-CARs, BCAA-derived metabolites.
    RESULTS: Using metabolic profiling, we found that BCAA starvation leads to massive triglyceride (TG) synthesis and LD accumulation. This was associated with the suppression of activated FA transport into the mitochondrial matrix. The suppression of FA import into mitochondria was rescued with the inhibitor of the acetyl-CoA carboxylase (ACC) and the activator of AMP kinase (AMPK), which both regulate carnitine palmitoyltransferase 1A (CPT1) activation status.
    CONCLUSIONS: Our data suggest that BCAA catabolism is required for the import of long chain carnitines (LC-CARs) into mitochondria, whereas the disruption of this link results in the redirection of activated FAs into TG synthesis and its deposition into LDs. We propose that this mechanism protects cells against mitochondrial overload with LC-CARs and it might be part of the universal reaction to amino acid perturbations during cancer growth, regulating FA handling and storage.
    Keywords:  BCAA metabolism; Fatty acid/Transport; Fluorescence microscopy; Lipid droplets; Lipidomics; Mitochondria; Pancreatic cancer; Triglycerides
    DOI:  https://doi.org/10.1186/s40170-024-00335-5
  35. Neurology. 2024 Apr 23. 102(8): e209243
    Clinical Characteristics, Developmental Trajectory, and Caregiver Burden of Patients With Creatine Transporter Deficiency (SLC6A8).
    Aurore Curie, Laurence Lion-François, Vassili Valayannopoulos, Nathalie Perreton, Marie Gavanon, Nathalie Touil, Amandine Brun-Laurisse, Fahra Gheurbi, Marion Buchy, Hulya Halep, David Cheillan, Catherine Mercier, Anaïs Brassier, Béatrice Desnous, Behrouz Kassai, Pascale De Lonlay, Vincent Des Portes.
      BACKGROUND AND OBJECTIVES: Creatine transporter deficiency (CTD) is a rare X-linked genetic disorder characterized by intellectual disability (ID). We evaluated the clinical characteristics and trajectory of patients with CTD and the impact of the disease on caregivers to identify relevant endpoints for future therapeutic trials.METHODS: As part of a French National Research Program, patients with CTD were included based on (1) a pathogenic SLC6A8 variant and (2) ID and/or autism spectrum disorder. Families and patients were referred by the physician who ordered the genetic analysis through Reference Centers of ID from rare causes and inherited metabolic diseases. After we informed the patients and their parents/guardians about the study, all of them gave written consent and were included. A control group of age-matched and sex-matched patients with Fragile X syndrome was also included. Physical examination, neuropsychological assessments, and caregiver impact were assessed. All data were analyzed using R software.
    RESULTS: Thirty-one patients (27 male, 4 female) were included (25/31 aged 18 years or younger). Most of the patients (71%) had symptoms at <24 months of age. The mean age at diagnosis was 6.5 years. Epilepsy occurred in 45% (mean age at onset: 8 years). Early-onset behavioral disorder occurred in 82%. Developmental trajectory was consistently delayed (fine and gross motor skills, language, and communication/sociability). Half of the patients with CTD had axial hypotonia during the first year of life. All patients were able to walk without help, but 7/31 had ataxia and only 14/31 could walk tandem gait. Most of them had abnormal fine motor skills (27/31), and most of them had language impairment (30/31), but 12/23 male patients (52.2%) completed the Peabody Picture Vocabulary Test. Approximately half (14/31) had slender build. Most of them needed nursing care (20/31), generally 1-4 h/d. Adaptive assessment (Vineland) confirmed that male patients with CTD had moderate-to-severe ID. Most caregivers (79%) were at risk of burnout, as shown by Caregiver Burden Inventory (CBI) > 36 (significantly higher than for patients with Fragile X syndrome) with a high burden of time dependence.
    DISCUSSION: In addition to clinical endpoints, such as the assessment of epilepsy and the developmental trajectory of the patient, the Vineland scale, PPVT5, and CBI are of particular interest as outcome measures for future trials.
    TRIAL REGISTRATION INFORMATION: ANSM Registration Number 2010-A00327-32.
    DOI:  https://doi.org/10.1212/WNL.0000000000209243
  36. Nitric Oxide. 2024 Mar 21. pii: S1089-8603(24)00039-9. [Epub ahead of print]146 19-23
    Sulfide catabolism in hibernation and neuroprotection.
    Fumito Ichinose, Allyson Hindle.
      The mammalian brain is exquisitely vulnerable to lack of oxygen. However, the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. In this narrative review, we present a case for sulfide catabolism as a key defense mechanism of the brain against acute oxygen shortage. We will examine literature on the role of sulfide in hypoxia/ischemia, deep hibernation, and leigh syndrome patients, and present our recent data that support the neuroprotective effects of sulfide catabolism and persulfide production. When oxygen levels become low, hydrogen sulfide (H2S) accumulates in brain cells and impairs the ability of these cells to use the remaining, available oxygen to produce energy. In recent studies, we found that hibernating ground squirrels, which can withstand very low levels of oxygen, have high levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize hydrogen sulfide in the brain. Silencing SQOR increased the sensitivity of the brain of squirrels and mice to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury in mice. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological agents that scavenge sulfide and/or increase persulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to ischemic injury to the brain or spinal cord. Drugs that oxidize hydrogen sulfide and/or increase persulfide may prove to be an effective approach to the treatment of patients experiencing brain injury caused by oxygen deprivation or mitochondrial dysfunction.
    DOI:  https://doi.org/10.1016/j.niox.2024.03.002
  37. Pediatr Res. 2024 Mar 22.
    Perinatal compromise affects development, form, and function of the hippocampus part one; clinical studies.
    Tegan A White, Suzanne L Miller, Amy E Sutherland, Beth J Allison, Emily J Camm.
      The hippocampus is a neuron-rich specialised brain structure that plays a central role in the regulation of emotions, learning and memory, cognition, spatial navigation, and motivational processes. In human fetal development, hippocampal neurogenesis is principally complete by mid-gestation, with subsequent maturation comprising dendritogenesis and synaptogenesis in the third trimester of pregnancy and infancy. Dendritogenesis and synaptogenesis underpin connectivity. Hippocampal development is exquisitely sensitive to perturbations during pregnancy and at birth. Clinical investigations demonstrate that preterm birth, fetal growth restriction (FGR), and acute hypoxic-ischaemic encephalopathy (HIE) are common perinatal complications that alter hippocampal development. In turn, deficits in hippocampal development and structure mediate a range of neurodevelopmental disorders, including cognitive and learning problems, autism, and Attention-Deficit/Hyperactivity Disorder (ADHD). In this review, we summarise the developmental profile of the hippocampus during fetal and neonatal life and examine the hippocampal deficits observed following common human pregnancy complications. IMPACT: The review provides a comprehensive summary of the developmental profile of the hippocampus in normal fetal and neonatal life. We address a significant knowledge gap in paediatric research by providing a comprehensive summary of the relationship between pregnancy complications and subsequent hippocampal damage, shedding new light on this critical aspect of early neurodevelopment.
    DOI:  https://doi.org/10.1038/s41390-024-03105-7
  38. Eur J Cell Biol. 2024 Mar 21. pii: S0171-9335(24)00023-2. [Epub ahead of print]103(2): 151406
    The solute carrier SLC7A1 may act as a protein transporter at the blood-brain barrier.
    Magdalena Kurtyka, Frank Wessely, Sarah Bau, Eseoghene Ifie, Liqun He, Nienke M de Wit, Alberte Bay Villekjær Pedersen, Maximilian Keller, Caleb Webber, Helga E de Vries, Olaf Ansorge, Christer Betsholtz, Marijke De Bock, Catarina Chaves, Birger Brodin, Morten S Nielsen, Winfried Neuhaus, Robert D Bell, Tamás Letoha, Axel H Meyer, Germán Leparc, Martin Lenter, Dominique Lesuisse, Zameel M Cader, Stephen T Buckley, Irena Loryan, Claus U Pietrzik.
      Despite extensive research, targeted delivery of substances to the brain still poses a great challenge due to the selectivity of the blood-brain barrier (BBB). Most molecules require either carrier- or receptor-mediated transport systems to reach the central nervous system (CNS). These transport systems form attractive routes for the delivery of therapeutics into the CNS, yet the number of known brain endothelium-enriched receptors allowing the transport of large molecules into the brain is scarce. Therefore, to identify novel BBB targets, we combined transcriptomic analysis of human and murine brain endothelium and performed a complex screening of BBB-enriched genes according to established selection criteria. As a result, we propose the high-affinity cationic amino acid transporter 1 (SLC7A1) as a novel candidate for transport of large molecules across the BBB. Using RNA sequencing and in situ hybridization assays, we demonstrated elevated SLC7A1 gene expression in both human and mouse brain endothelium. Moreover, we confirmed SLC7A1 protein expression in brain vasculature of both young and aged mice. To assess the potential of SLC7A1 as a transporter for larger proteins, we performed internalization and transcytosis studies using a radiolabelled or fluorophore-labelled anti-SLC7A1 antibody. Our results showed that SLC7A1 internalised a SLC7A1-specific antibody in human colorectal carcinoma (HCT116) cells. Moreover, transcytosis studies in both immortalised human brain endothelial (hCMEC/D3) cells and primary mouse brain endothelial cells clearly demonstrated that SLC7A1 effectively transported the SLC7A1-specific antibody from luminal to abluminal side. Therefore, here in this study, we present for the first time the SLC7A1 as a novel candidate for transport of larger molecules across the BBB.
    Keywords:  BBB; CAT-1; SLC7A1; brain drug delivery; brain therapeutics; solute carriers
    DOI:  https://doi.org/10.1016/j.ejcb.2024.151406
  39. J Neurol. 2024 Mar 28.
    Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
    Tomas Ferreira, Kiran Polavarapu, Catarina Olimpio, Ida Paramonov, Hanns Lochmüller, Rita Horvath.
      BACKGROUND: Peripheral neuropathies in mitochondrial disease are caused by mutations in nuclear genes encoding mitochondrial proteins, or in the mitochondrial genome. Whole exome or genome sequencing enable parallel testing of nuclear and mtDNA genes, and it has significantly advanced the genetic diagnosis of inherited diseases. Despite this, approximately 40% of all Charcot-Marie-Tooth (CMT) cases remain undiagnosed.METHODS: The genome-phenome analysis platform (GPAP) in RD-Connect was utilised to create a cohort of 2087 patients with at least one Human Phenotype Ontology (HPO) term suggestive of a peripheral neuropathy, from a total of 10,935 patients. These patients' genetic data were then analysed and searched for variants in known mitochondrial disease genes.
    RESULTS: A total of 1,379 rare variants were identified, 44 of which were included in this study as either reported pathogenic or likely causative in 42 patients from 36 families. The most common genes found to be likely causative for an autosomal dominant neuropathy were GDAP1 and GARS1. We also detected heterozygous likely pathogenic variants in DNA2, MFN2, DNM2, PDHA1, SDHA, and UCHL1. Biallelic variants in SACS, SPG7, GDAP1, C12orf65, UCHL1, NDUFS6, ETFDH and DARS2 and variants in the mitochondrial DNA (mtDNA)-encoded MT-ATP6 and MT-TK were also causative for mitochondrial CMT. Only 50% of these variants were already reported as solved in GPAP.
    CONCLUSION: Variants in mitochondrial disease genes are frequent in patients with inherited peripheral neuropathies. Due to the clinical overlap between mitochondrial disease and CMT, agnostic exome or genome sequencing have better diagnostic yields than targeted gene panels.
    Keywords:  CMT; Genetic heterogeneity; Genome-phenome analysis platform (GPAP); Mitochondrial disease; Peripheral neuropathies; Rare variants
    DOI:  https://doi.org/10.1007/s00415-024-12319-y
  40. Eur J Med Res. 2024 Mar 25. 29(1): 199
    Cortical lipid metabolic pathway alteration of early Alzheimer's disease and candidate drugs screen.
    Linshuang Wang, Fengxue Qu, Xueyun Yu, Sixia Yang, Binbin Zhao, Yaojing Chen, Pengbo Li, Zhanjun Zhang, Junying Zhang, Xuejie Han, Dongfeng Wei.
      BACKGROUND: Lipid metabolism changes occur in early Alzheimer's disease (AD) patients. Yet little is known about metabolic gene changes in early AD cortex.METHODS: The lipid metabolic genes selected from two datasets (GSE39420 and GSE118553) were analyzed with enrichment analysis. Protein-protein interaction network construction and correlation analyses were used to screen core genes. Literature analysis and molecular docking were applied to explore potential therapeutic drugs.
    RESULTS: 60 lipid metabolic genes differentially expressed in early AD patients' cortex were screened. Bioinformatics analyses revealed that up-regulated genes were mainly focused on mitochondrial fatty acid oxidation and mediating the activation of long-chain fatty acids, phosphoproteins, and cholesterol metabolism. Down-regulated genes were mainly focused on lipid transport, carboxylic acid metabolic process, and neuron apoptotic process. Literature reviews and molecular docking results indicated that ACSL1, ACSBG2, ACAA2, FABP3, ALDH5A1, and FFAR4 were core targets for lipid metabolism disorder and had a high binding affinity with compounds including adenosine phosphate, oxidized Photinus luciferin, BMS-488043, and candidate therapeutic drugs especially bisphenol A, benzo(a)pyrene, ethinyl estradiol.
    CONCLUSIONS: AD cortical lipid metabolism disorder was associated with the dysregulation of the PPAR signaling pathway, glycerophospholipid metabolism, adipocytokine signaling pathway, fatty acid biosynthesis, fatty acid degradation, ferroptosis, biosynthesis of unsaturated fatty acids, and fatty acid elongation. Candidate drugs including bisphenol A, benzo(a)pyrene, ethinyl estradiol, and active compounds including adenosine phosphate, oxidized Photinus luciferin, and BMS-488043 have potential therapeutic effects on cortical lipid metabolism disorder of early AD.
    Keywords:  Alzheimer’s disease; Bioinformatics; Candidate compounds; Cortex; Early-onset; Lipid metabolism disorder
    DOI:  https://doi.org/10.1186/s40001-024-01730-w
  41. Exp Brain Res. 2024 Mar 25.
    [3H]-NFPS binding to the glycine transporter 1 in the hemi-parkinsonian rat brain.
    Imane Frouni, Esther Kim, Judy Shaqfah, Dominique Bédard, Cynthia Kwan, Sébastien Belliveau, Philippe Huot.
      L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [3H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD.
    Keywords:  6-OHDA-lesioned rat; Autoradiography; Dyskinesia; GlyT1; Org-25,935; Parkinson’s disease; [3H]-NFPS
    DOI:  https://doi.org/10.1007/s00221-024-06815-w
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