bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2024–06–02
nineteen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. D-ꞵ-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.
  2. Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD.
  3. Glucose transporter-1 deficiency syndrome with extreme phenotypic variability in a five-generation family carrying a novel SLC2A1 variant.
  4. Lipidome atlas of the adult human brain.
  5. Four-dimensional Lipidomics Profiling in X-linked Adrenoleukodystrophy using Trapped Ion Mobility Mass Spectrometry.
  6. Long-term demyelination and aging-associated changes in mice corpus callosum; evidence for the role of accelerated aging in remyelination failure in a mouse model of multiple sclerosis.
  7. Synaptic signaling modeled by functional connectivity predicts metabolic demands of the human brain.
  8. Localized Pantothenic Acid (Vitamin B5) Reductions Present Throughout the Dementia with Lewy Bodies Brain.
  9. Neurometabolite differences in Autism as assessed with Magnetic Resonance Spectroscopy: A systematic review and meta-analysis.
  10. Fatty Acid Metabolism in Peroxisomes and Related Disorders.
  11. Identifying Metabolic Diseases That Precipitate Neonatal Seizures.
  12. Multiscale metabolomics techniques: Insights into neuroscience research.
  13. Rab30 facilitates lipid homeostasis during fasting.
  14. The N-terminal signature motif on the transporter MCT1 is critical for CD147-mediated trafficking.
  15. Nutritional roles and therapeutic potentials of dietary sphingomyelin in brain diseases.
  16. Eicosanoid Signaling in Neuroinflammation Associated with Alzheimer's Disease.
  17. L-serine deficiency: on the properties of the Asn133Ser variant of human phosphoserine phosphatase.
  18. Regulation of mitochondrial dysfunction by estrogens and estrogen receptors in Alzheimer's disease: A focused review.
  19. 13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.
  1. PNAS Nexus. 2024 May;3(5): pgae196
    D-ꞵ-hydroxybutyrate stabilizes hippocampal CA3-CA1 circuit during acute insulin resistance.
    Bartosz Kula, Botond Antal, Corey Weistuch, Florian Gackière, Alexander Barre, Victor Velado, Jeffrey M Hubbard, Maria Kukley, Lilianne R Mujica-Parodi, Nathan A Smith.
      The brain primarily relies on glycolysis for mitochondrial respiration but switches to alternative fuels such as ketone bodies (KBs) when less glucose is available. Neuronal KB uptake, which does not rely on glucose transporter 4 (GLUT4) or insulin, has shown promising clinical applicability in alleviating the neurological and cognitive effects of disorders with hypometabolic components. However, the specific mechanisms by which such interventions affect neuronal functions are poorly understood. In this study, we pharmacologically blocked GLUT4 to investigate the effects of exogenous KB D-ꞵ-hydroxybutyrate (D-ꞵHb) on mouse brain metabolism during acute insulin resistance (AIR). We found that both AIR and D-ꞵHb had distinct impacts across neuronal compartments: AIR decreased synaptic activity and long-term potentiation (LTP) and impaired axonal conduction, synchronization, and action potential properties, while D-ꞵHb rescued neuronal functions associated with axonal conduction, synchronization, and LTP.
    Keywords:  GLUT4; beta-hydroxybutyrate; hippocampus; insulin resistance; ketone bodies
    DOI:  https://doi.org/10.1093/pnasnexus/pgae196
  2. Res Sq. 2024 May 14. pii: rs.3.rs-4373201. [Epub ahead of print]
    Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD.
    Shaowei Wang, Boyang Li, Zhiheng Cai, Cristelle Hugo, Jie Li, Yi Sun, Lu Qian, Alan T Remaley, Julia Tcw, Helena C Chui, David A Bennett, Zoe Arvanitakis, Bilal Kerman, Hussein Yassine.
      Background Cellular senescence is a hallmark of aging and has been implicated in Alzheimer's disease (AD) pathogenesis. Cholesterol accumulation drives cellular senescence; however, the underlying mechanisms are unclear. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis. ABCA1 expression and its trafficking is altered in APOE4 and AD cellular and mouse models. However, whether ABCA1 trafficking is involved in cellular senescence in APOE4 and AD remains unknown. Methods We examined the association between cellular senescence and ABCA1 expression in human postmortem brain samples using transcriptomic, histological, and biochemical analyses. An unbiased proteomic screening was performed to identify targets that mediate cellular ABCA1 trafficking. APOE4-TR mice, immortalized, primary and induced pluripotent stem cell (iPSC) models were used to examine the cholesterol-ABCA1-senescence pathways. Results Bulk and single nuclei transcriptomic profiling of the human dorsolateral prefrontal cortex from the Religious Order Study/Memory Aging Project (ROSMAP) revealed upregulation of cellular senescence transcriptome signatures in AD, which was strongly correlated with ABCA1 expression. Immunofluorescence and immunoblotting analyses confirmed increased ABCA1 expression in AD brain tissues, which was associated with lipofuscin-stained lipids and mTOR phosphorylation. Using discovery proteomics, caveolin-1, a sensor of cellular cholesterol accumulation, was identified to promote ABCA1 endolysosomal trafficking. Greater caveolin-1 expression was found in both APOE4-TR mouse models and AD human brains. Cholesterol induced mTORC1 activation was regulated by ABCA1 expression or its lysosomal trapping. Reducing cholesterol by cyclodextrin in APOE4-TR mice reduced ABCA1 lysosome trapping and increased ABCA1 recycling to efflux cholesterol to HDL particles, reducing mTORC1 activation and senescence-associated neuroinflammation. In human iPSC-derived astrocytes, the reduction of cholesterol by cyclodextrin attenuated inflammatory responses. Conclusions Cholesterol accumulation in APOE4 and AD induced caveolin-1 expression, which traps ABCA1 in lysosomes to activate mTORC1 pathways and induce cellular senescence. This study provided novel insights into how cholesterol accumulation in APOE4 and AD accelerates senescence.
    DOI:  https://doi.org/10.21203/rs.3.rs-4373201/v1
  3. Eur J Neurol. 2024 May 27. e16325
    Glucose transporter-1 deficiency syndrome with extreme phenotypic variability in a five-generation family carrying a novel SLC2A1 variant.
    Alessia Giugno, Elena Falcone, Francesco Fortunato, Ilaria Sammarra, Radha Procopio, Monica Gagliardi, Alessia Bauleo, Laura de Stefano, Iolanda Martino, Antonio Gambardella.
       BACKGROUND AND PURPOSE: Glucose transporter-1 (GLUT1) deficiency syndrome (GLUT1-DS) is a metabolic disorder due to reduced expression of GLUT1, a glucose transporter of the central nervous system. GLUT1-DS is caused by heterozygous SLC2A1 variants that mostly arise de novo. Here, we report a large family with heterogeneous phenotypes related to a novel SLC2A1 variant.
    METHODS: We present clinical and genetic features of a five-generation family with GLUT1-DS.
    RESULTS: The 14 (nine living) affected members had heterogeneous phenotypes, including seizures (11/14), behavioral disturbances (5/14), mild intellectual disability (3/14), and/or gait disabilities (2/14). Brain magnetic resonance imaging revealed hippocampal sclerosis in the 8-year-old proband, who also had drug-responsive absences associated with attention-deficit/hyperactivity disorder. His 52-year-old father, who had focal epilepsy since childhood, developed paraparesis related to a reversible myelitis associated with hypoglycorrhachia. Molecular study detected a novel heterozygous missense variant (c.446C>T) in exon 4 of SLC2A1 (NM: 006516.2) that cosegregated with the illness. This variant causes an amino acid replacement (p.Pro149Leu) at the fourth transmembrane segment of GLUT1, an important domain located at its catalytic core.
    CONCLUSIONS: Our study illustrates the extremely heterogenous phenotypes in familial GLUT1-DS, ranging from milder classic phenotypes to more subtle neurological disorder including paraparesis. This novel SLC2A1 variant (c.446C>T) provides new insight into the pathophysiology of GLUT1-DS.
    Keywords:  GLUT1 deficiency syndrome; SLC2A1 gene; childhood absence epilepsy; hippocampal sclerosis; missense variant
    DOI:  https://doi.org/10.1111/ene.16325
  4. Nat Commun. 2024 May 25. 15(1): 4455
    Lipidome atlas of the adult human brain.
    Maria Osetrova, Anna Tkachev, Waltraud Mair, Patricia Guijarro Larraz, Olga Efimova, Ilia Kurochkin, Elena Stekolshchikova, Nickolay Anikanov, Juat Chin Foo, Amaury Cazenave-Gassiot, Aleksandra Mitina, Polina Ogurtsova, Song Guo, Daria M Potashnikova, Alexander A Gulin, Alexander A Vasin, Anastasia Sarycheva, Gleb Vladimirov, Maria Fedorova, Yury Kostyukevich, Evgeny Nikolaev, Markus R Wenk, Ekaterina E Khrameeva, Philipp Khaitovich.
      Lipids are the most abundant but poorly explored components of the human brain. Here, we present a lipidome map of the human brain comprising 75 regions, including 52 neocortical ones. The lipidome composition varies greatly among the brain regions, affecting 93% of the 419 analyzed lipids. These differences reflect the brain's structural characteristics, such as myelin content (345 lipids) and cell type composition (353 lipids), but also functional traits: functional connectivity (76 lipids) and information processing hierarchy (60 lipids). Combining lipid composition and mRNA expression data further enhances functional connectivity association. Biochemically, lipids linked with structural and functional brain features display distinct lipid class distribution, unsaturation extent, and prevalence of omega-3 and omega-6 fatty acid residues. We verified our conclusions by parallel analysis of three adult macaque brains, targeted analysis of 216 lipids, mass spectrometry imaging, and lipidome assessment of sorted murine neurons.
    DOI:  https://doi.org/10.1038/s41467-024-48734-y
  5. J Lipid Res. 2024 May 23. pii: S0022-2275(24)00072-5. [Epub ahead of print] 100567
    Four-dimensional Lipidomics Profiling in X-linked Adrenoleukodystrophy using Trapped Ion Mobility Mass Spectrometry.
    Yorrick R J Jaspers, Sven W Meyer, Mia L Pras-Raves, Inge M E Dijkstra, Eric J M Wever, Adrie D Dane, Jan-Bert van Klinken, Gajja S Salomons, Riekelt H Houtkooper, Marc Engelen, Stephan Kemp, Michel Van Weeghel, Frédéric M Vaz.
      Lipids play pivotal roles in an extensive range of metabolic and physiological processes. In recent years, the convergence of trapped ion mobility (TIMS) and mass spectrometry (MS) has enabled 4D-lipidomics, a highly promising technology for comprehensive lipid analysis. 4D-lipidomics assesses lipid annotations across four distinct dimensions-retention time, collisional cross section, m/z (mass-to-charge ratio), and MS/MS spectra-providing a heightened level of confidence in lipid annotation. These advantages prove particularly valuable when investigating complex disorders involving lipid metabolism, such as adrenoleukodystrophy (ALD). ALD is characterized by the accumulation of very-long-chain fatty acids (VLCFA) due to pathogenic variants in the ABCD1 gene. A comprehensive 4D-lipidomics strategy of ALD fibroblasts demonstrated significant elevations of various lipids from multiple classes. This indicates that the changes observed in ALD are not confined to a single lipid class and likely impacts a broad spectrum of lipid-mediated physiological processes. Our findings highlight the incorporation of mainly saturated and monounsaturated VLCFA variants into a range of lipid classes, encompassing phosphatidylcholines, triacylglycerols, and cholesterol esters. These include ultra-long-chain fatty acids with a length of up to thirty carbon atoms. Lipid species containing C26:0, C26:1 were the most frequently detected VLCFA lipids in our study. Furthermore, we report a panel of 121 new candidate biomarkers in fibroblasts, exhibiting significant differentiation between controls and individuals with ALD. In summary, this study demonstrates the capabilities of a 4D-lipid profiling workflow in unraveling novel insights into the intricate lipid modifications associated with metabolic disorders like ALD.
    Keywords:  4D-Lipidomics; PASEF; VLCFA; adrenoleukodystrophy; mass spectrometry; trapped ion mobility spectrometry; very long-chain fatty acids
    DOI:  https://doi.org/10.1016/j.jlr.2024.100567
  6. Aging Cell. 2024 May 28. e14211
    Long-term demyelination and aging-associated changes in mice corpus callosum; evidence for the role of accelerated aging in remyelination failure in a mouse model of multiple sclerosis.
    Elham Parandavar, Mahshid Shafizadeh, Shahin Ahmadian, Mohammad Javan.
      Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder affecting the central nervous system. Evidence suggests that age-related neurodegeneration contributes to disability progression during the chronic stages of MS. Aging is characterized by decreased regeneration potential and impaired myelin repair in the brain. It is hypothesized that accelerated cellular aging contributes to the functional decline associated with neurodegenerative diseases. We assessed the impact of aging on myelin content in the corpus callosum (CC) and compared aging with the long-term demyelination (LTD) consequents induced by 12 weeks of feeding with a cuprizone (CPZ) diet. Initially, evaluating myelin content in 2-, 6-, and 18-month-old mice revealed a reduction in myelin content, particularly at 18 months. Myelin thickness was decreased and the g-ratio increased in aged mice. Although a lower myelin content and higher g-ratio were observed in LTD model mice, compared to the normally aged mice, both aging and LTD exhibited relatively similar myelin ultrastructure. Our findings provide evidence that LTD exhibits the hallmarks of aging such as elevated expression of senescence-associated genes, mitochondrial dysfunction, and high level of oxidative stress as observed following normal aging. We also investigated the senescence-associated β-galactosidase activity in O4+ late oligodendrocyte progenitor cells (OPCs). The senescent O4+/β-galactosidase+ cells were elevated in the CPZ diet. Our data showed that the myelin degeneration in CC occurs throughout the lifespan, and LTD induced by CPZ accelerates the aging process which may explain the impairment of myelin repair in patients with progressive MS.
    Keywords:  cellular aging; cuprizone; long‐term demyelination; multiple sclerosis; myelin repair impairment; oligodendrocyte progenitor cells; remyelination
    DOI:  https://doi.org/10.1111/acel.14211
  7. Neuroimage. 2024 May 27. pii: S1053-8119(24)00153-8. [Epub ahead of print] 120658
    Synaptic signaling modeled by functional connectivity predicts metabolic demands of the human brain.
    Sebastian Klug, Matej Murgaš, Godber M Godbersen, Marcus Hacker, Rupert Lanzenberger, Andreas Hahn.
       PURPOSE: The human brain is characterized by interacting large-scale functional networks fueled by glucose metabolism. Since former studies could not sufficiently clarify how these functional connections shape glucose metabolism, we aimed to provide a neurophysiologically-based approach.
    METHODS: 51 healthy volunteers underwent simultaneous PET/MRI to obtain BOLD functional connectivity and [18F]FDG glucose metabolism. These multimodal imaging proxies of fMRI and PET were combined in a whole-brain extension of metabolic connectivity mapping. Specifically, functional connectivity of all brain regions were used as input to explain glucose metabolism of a given target region. This enabled the modeling of postsynaptic energy demands by incoming signals from distinct brain regions.
    RESULTS: Functional connectivity input explained a substantial part of metabolic demands but with pronounced regional variations (34 - 76%). During cognitive task performance this multimodal association revealed a shift to higher network integration compared to resting state. In healthy aging, a dedifferentiation (decreased segregated/modular structure of the brain) of brain networks during rest was observed. Furthermore, by including data from mRNA maps, [11C]UCB-J synaptic density and aerobic glycolysis (oxygen-to-glucose index from PET data), we show that whole-brain functional input reflects non-oxidative, on-demand metabolism of synaptic signaling. The metabolically-derived directionality of functional inputs further marked them as top-down predictions. In addition, the approach uncovered formerly hidden networks with superior efficiency through metabolically informed network partitioning.
    CONCLUSIONS: Applying multimodal imaging, we decipher a crucial part of the metabolic and neurophysiological basis of functional connections in the brain as interregional on-demand synaptic signaling fueled by anaerobic metabolism. The observed task- and age-related effects indicate promising future applications to characterize human brain function and clinical alterations.
    Keywords:  Simultaneous PET/MRI; brain metabolism; functional PET; functional connectivity; metabolic connectivity mapping
    DOI:  https://doi.org/10.1016/j.neuroimage.2024.120658
  8. J Parkinsons Dis. 2024 May 24.
    Localized Pantothenic Acid (Vitamin B5) Reductions Present Throughout the Dementia with Lewy Bodies Brain.
    Melissa Scholefield, Stephanie J Church, Jingshu Xu, Stefano Patassini, Garth J S Cooper.
       Background: Localized pantothenic acid deficiencies have been observed in several neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease dementia (PDD), and Huntington's disease (HD), indicating downstream energetic pathway perturbations. However, no studies have yet been performed to see whether such deficiencies occur across the dementia with Lewy bodies (DLB) brain, or what the pattern of such dysregulation may be.
    Objective: Firstly, this study aimed to quantify pantothenic acid levels across ten regions of the brain in order to determine the localization of any pantothenic acid dysregulation in DLB. Secondly, the localization of pantothenic acid alterations was compared to that previously in AD, PDD, and HD brains.
    Methods: Pantothenic acid levels were determined in 20 individuals with DLB and 19 controls by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) across ten brain regions. Case-control differences were determined by nonparametric Mann-Whitney U test, with the calculation of S-values, risk ratios, E-values, and effect sizes. The results were compared with those previously obtained in DLB, AD, and HD.
    Results: Pantothenic acid levels were significantly decreased in six of the ten investigated brain regions: the pons, substantia nigra, motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. This level of pantothenic acid dysregulation is most similar to that of the AD brain, in which pantothenic acid is also decreased in the motor cortex, middle temporal gyrus, primary visual cortex, and hippocampus. DLB appears to differ from other neurodegenerative diseases in being the only of the four to not show pantothenic acid dysregulation in the cerebellum.
    Conclusions: Pantothenic acid deficiency appears to be a shared mechanism of several neurodegenerative diseases, although differences in the localization of this dysregulation may contribute to the differing clinical pathways observed in these conditions.
    Keywords:   Lewy body dementia ; mass spectrometry ; Pantothenic acid; UHPLC–MS/MS; dementia with Lewy bodies; metabolomics; vitamin B5
    DOI:  https://doi.org/10.3233/JPD-240075
  9. Neurosci Biobehav Rev. 2024 May 23. pii: S0149-7634(24)00197-0. [Epub ahead of print]162 105728
    Neurometabolite differences in Autism as assessed with Magnetic Resonance Spectroscopy: A systematic review and meta-analysis.
    Alice R Thomson, Duanghathai Pasanta, Tomoki Arichi, Nicolaas A Puts.
      1H-Magnetic Resonance Spectroscopy (MRS) is a non-invasive technique that can be used to quantify the concentrations of metabolites in the brain in vivo. MRS findings in the context of autism are inconsistent and conflicting. We performed a systematic review and meta-analysis of MRS studies measuring glutamate and gamma-aminobutyric acid (GABA), as well as brain metabolites involved in energy metabolism (glutamine, creatine), neural and glial integrity (e.g. n-acetyl aspartate (NAA), choline, myo-inositol) and oxidative stress (glutathione) in autism cohorts. Data were extracted and grouped by metabolite, brain region and several other factors before calculation of standardised effect sizes. Overall, we find significantly lower concentrations of GABA and NAA in autism, indicative of disruptions to the balance between excitation/inhibition within brain circuits, as well as neural integrity. Further analysis found these alterations are most pronounced in autistic children and in limbic brain regions relevant to autism phenotypes. Additionally, we show how study outcome varies due to demographic and methodological factors , emphasising the importance of conforming with standardised consensus study designs and transparent reporting.
    Keywords:  Autism; E/I balance; Edited MRS; GABA; Glutamate; Metabolites; Neurodevelopment
    DOI:  https://doi.org/10.1016/j.neubiorev.2024.105728
  10. Adv Exp Med Biol. 2024 May 30.
    Fatty Acid Metabolism in Peroxisomes and Related Disorders.
    Katsuya Morito, Hanif Ali, Shigenobu Kishino, Tamotsu Tanaka.
      One of the functions of peroxisomes is the oxidation of fatty acids (FAs). The importance of this function in our lives is evidenced by the presence of peroxisomal disorders caused by the genetic deletion of proteins involved in these processes. Unlike mitochondrial oxidation, peroxisomal oxidation is not directly linked to ATP production. What is the role of FA oxidation in peroxisomes? Recent studies have revealed that peroxisomes supply the building blocks for lipid synthesis in the endoplasmic reticulum and facilitate intracellular carbon recycling for membrane quality control. Accumulation of very long-chain fatty acids (VLCFAs), which are peroxisomal substrates, is a diagnostic marker in many types of peroxisomal disorders. However, the relationship between VLCFA accumulation and various symptoms of these disorders remains unclear. Recently, we developed a method for solubilizing VLCFAs in aqueous media and found that VLCFA toxicity could be mitigated by oleic acid replenishment. In this chapter, we present the physiological role of peroxisomal FA oxidation and the knowledge obtained from VLCFA-accumulating peroxisome-deficient cells.
    Keywords:  Cell toxicity; Oleic acid; Peroxisomal disorder; Very long-chain fatty acid; α-Oxidation; β-Oxidation
    DOI:  https://doi.org/10.1007/5584_2024_802
  11. Neonatal Netw. 2024 May 01. 43(3): 139-147
    Identifying Metabolic Diseases That Precipitate Neonatal Seizures.
    Rebecca L Judy, Joanna L Reynolds, Amy J Jnah.
      Although a rare cause of neonatal seizures, inborn errors of metabolism (IEMs) remain an essential component of a comprehensive differential diagnosis for poorly controlled neonatal epilepsy. Diagnosing neonatal-onset metabolic conditions proves a difficult task for clinicians; however, routine state newborn screening panels now include many IEMs. Three in particular-pyridoxine-dependent epilepsy, maple syrup urine disease, and Zellweger spectrum disorders-are highly associated with neonatal epilepsy and neurocognitive injury yet are often misdiagnosed. As research surrounding biomarkers for these conditions is emerging and gene sequencing technologies are advancing, clinicians are beginning to better establish early identification strategies for these diseases. In this literature review, the authors aim to present clinicians with an innovative clinical guide highlighting IEMs associated with neonatal-onset seizures, with the goal of promoting quality care and safety.
    Keywords:  Zellweger spectrum disorders; epilepsy; inborn error of metabolism; maple syrup urine disease; metabolic; neonatal seizures; pyridoxine-dependent epilepsy
    DOI:  https://doi.org/10.1891/NN-2023-0048
  12. Neurobiol Dis. 2024 May 26. pii: S0969-9961(24)00140-2. [Epub ahead of print] 106541
    Multiscale metabolomics techniques: Insights into neuroscience research.
    Xiaoya Wang, Ruiyun Peng, Li Zhao.
      The field of metabolomics examines the overall composition and dynamic patterns of metabolites in living organisms. The primary methods used in metabolomics include liquid chromatography (LC), nuclear magnetic resonance (NMR), and mass spectrometry (MS) analysis. These methods enable the identification and examination of metabolite types and contents within organisms, as well as modifications to metabolic pathways and their connection to the emergence of diseases. Research in metabolomics has extensive value in basic and applied sciences. The field of metabolomics is growing quickly, with the majority of studies concentrating on biomedicine, particularly early disease diagnosis, therapeutic management of human diseases, and mechanistic knowledge of biochemical processes. Multiscale metabolomics is an approach that integrates metabolomics techniques at various scales, including the holistic, tissue, cellular, and organelle scales, to enable more thorough and in-depth studies of metabolic processes in organisms. Multiscale metabolomics can be combined with methods from systems biology and bioinformatics. In recent years, multiscale metabolomics approaches have become increasingly important in neuroscience research due to the nervous system's high metabolic demands. Multiscale metabolomics can offer novel concepts and approaches for the diagnosis, treatment, and development of medication for neurological illnesses in addition to a more thorough understanding of brain metabolism and nervous system function. In this review, we summarize the use of multiscale metabolomics techniques in neuroscience, address the promise and constraints of these techniques, and provide an overview of the metabolome and its applications in neuroscience.
    Keywords:  Metabolomics; Metabolomics technology; Multiscale; Nervous system
    DOI:  https://doi.org/10.1016/j.nbd.2024.106541
  13. Nat Commun. 2024 May 25. 15(1): 4469
    Rab30 facilitates lipid homeostasis during fasting.
    Danielle M Smith, Brian Y Liu, Michael J Wolfgang.
      To facilitate inter-tissue communication and the exchange of proteins, lipoproteins, and metabolites with the circulation, hepatocytes have an intricate and efficient intracellular trafficking system regulated by small Rab GTPases. Here, we show that Rab30 is induced in the mouse liver by fasting, which is amplified in liver-specific carnitine palmitoyltransferase 2 knockout mice (Cpt2L-/-) lacking the ability to oxidize fatty acids, in a Pparα-dependent manner. Live-cell super-resolution imaging and in vivo proximity labeling demonstrates that Rab30-marked vesicles are highly dynamic and interact with proteins throughout the secretory pathway. Rab30 whole-body, liver-specific, and Rab30; Cpt2 liver-specific double knockout (DKO) mice are viable with intact Golgi ultrastructure, although Rab30 deficiency in DKO mice suppresses the serum dyslipidemia observed in Cpt2L-/- mice. Corresponding with decreased serum triglyceride and cholesterol levels, DKO mice exhibit decreased circulating but not hepatic ApoA4 protein, indicative of a trafficking defect. Together, these data suggest a role for Rab30 in the selective sorting of lipoproteins to influence hepatocyte and circulating triglyceride levels, particularly during times of excessive lipid burden.
    DOI:  https://doi.org/10.1038/s41467-024-48959-x
  14. J Biol Chem. 2024 May 22. pii: S0021-9258(24)01834-9. [Epub ahead of print]300(6): 107333
    The N-terminal signature motif on the transporter MCT1 is critical for CD147-mediated trafficking.
    Devin J Seka, Annika K Schulz, Tarjani M Thaker, Thomas M Tomasiak.
      The human Solute Carrier (SLC) family member, monocarboxylate transporter 1 (MCT1), transports lactic and pyruvic acid across biological membranes to regulate cellular pH and metabolism. Proper trafficking of MCT1 from the endoplasmic reticulum to the plasma membrane hinges on its interactions with the membrane-bound chaperone protein, CD147. Here, using AlphaFold2 modeling and copurification, we show how a conserved signature motif located in the flexible N-terminus of MCT1 is a crucial region of interaction between MCT1 and the C-terminus of CD147. Mutations to this motif-namely, the thymic cancer linked G19C and the highly conserved W20A-destabilize the MCT1-CD147 complex and lead to a loss of proper membrane localization and cellular substrate flux. Notably, the monomeric stability of MCT1 remains unaffected in mutants, thus supporting the role of CD147 in mediating the trafficking of the heterocomplex. Using the auxiliary chaperone, GP70, we demonstrated that W20A-MCT1 can be trafficked to the plasma membrane, while G19C-MCT1 remains internalized. Overall, our findings underscore the critical role of the MCT1 transmembrane one signature motif for engaging CD147 and identify altered chaperone binding mechanisms between the CD147 and GP70 glycoprotein chaperones.
    Keywords:  lactate; membrane complexes; monocarboxylate transporters; pyruvate; subcellular localization; thermostability; trafficking
    DOI:  https://doi.org/10.1016/j.jbc.2024.107333
  15. J Clin Biochem Nutr. 2024 May;74(3): 185-191
    Nutritional roles and therapeutic potentials of dietary sphingomyelin in brain diseases.
    Shoug Alashmali.
      Sphingolipids have recently gained interest as potential players in variety of diseases due to their import roles in human body particularly, the brain. As sphingomyelin is the most common type of sphingolipids, deficits in its distribution to brain cells may contribute to neurological anomalies. However, data is limited regarding the impact of different levels of dietary sphingomyelin intake on neural function especially if this approach can boost cognition and prevent neurological disorders. This review evaluates the effect of dietary sphingomyelin and its metabolites (ceramide and sphingosine-1-phosphate) in animal models and in humans, with a primary focus on its impact on brain health. Additionally, it proposes multiple neuroenhancing effects of sphingomyelin-rich diet. This presents an opportunity to stimulate further research that aims to determine the therapeutic value of dietary sphingomyelin in preventing, improving or slowing the progression of central nervous system disorders.
    Keywords:  brain health; dietary supplementation; disorders of the CNS; neuroenhancing effects; sphingomyelin
    DOI:  https://doi.org/10.3164/jcbn.23-97
  16. Eur J Pharmacol. 2024 May 29. pii: S0014-2999(24)00382-0. [Epub ahead of print] 176694
    Eicosanoid Signaling in Neuroinflammation Associated with Alzheimer's Disease.
    Koppada Lohitaksha, Deepika Kumari, Manas Shukla, Lavanya Byagari, Vigneshwar Reddy Ashireddygari, Prasad Tammineni, Pallu Reddanna, Madhavi Gorla.
      Alzheimer's disease (AD) is a prevalent neurodegenerative condition affecting a substantial portion of the global population. It is marked by a complex interplay of factors, including the accumulation of amyloid plaques and tau tangles within the brain, leading to neuroinflammation and neuronal damage. Recent studies have underscored the role of free lipids and their derivatives in the initiation and progression of AD. Eicosanoids, metabolites of polyunsaturated fatty acids like arachidonic acid (AA), emerge as key players in this scenario. Remarkably, eicosanoids can either promote or inhibit the development of AD, and this multifaceted role is determined by how eicosanoid signaling influences the immune responses within the brain. However, the precise molecular mechanisms dictating the dual role of eicosanoids in AD remain elusive. In this comprehensive review, we explore the intricate involvement of eicosanoids in neuronal function and dysfunction. Furthermore, we assess the therapeutic potential of targeting eicosanoid signaling pathways as a viable strategy for mitigating or halting the progression of AD.
    Keywords:  Alzheimer's disease (AD); Neuroinflammation; SPMs; arachidonic acid; cyclooxygenase; eicosanoids; leukotrienes; lipoxygenases; prostaglandins; thromboxanes
    DOI:  https://doi.org/10.1016/j.ejphar.2024.176694
  17. Sci Rep. 2024 05 30. 14(1): 12463
    L-serine deficiency: on the properties of the Asn133Ser variant of human phosphoserine phosphatase.
    Loredano Pollegioni, Barbara Campanini, Jean-Marc Good, Zoraide Motta, Giulia Murtas, Valeria Buoli Comani, Despina-Christina Pavlidou, Noëlle Mercier, Laureane Mittaz-Crettol, Silvia Sacchi, Francesco Marchesani.
      The non-essential amino acid L-serine is involved in a number of metabolic pathways and in the brain its level is largely due to the biosynthesis from the glycolytic intermediate D-3-phosphoglycerate by the phosphorylated pathway (PP). This cytosolic pathway is made by three enzymes proposed to generate a reversible metabolon named the "serinosome". Phosphoserine phosphatase (PSP) catalyses the last and irreversible step, representing the driving force pushing L-serine synthesis. Genetic defects of the PP enzymes result in strong neurological phenotypes. Recently, we identified the homozygous missense variant [NM_004577.4: c.398A > G p.(Asn133Ser)] in the PSPH, the PSP encoding gene, in two siblings with a neurodevelopmental syndrome and a myelopathy. The recombinant Asn133Ser enzyme does not show significant alterations in protein conformation and dimeric oligomerization state, as well as in enzymatic activity and functionality of the reconstructed PP. However, the Asn133Ser variant is less stable than wild-type PSP, a feature also apparent at cellular level. Studies on patients' fibroblasts also highlight a strong decrease in the level of the enzymes of the PP, a partial nuclear and perinuclear localization of variant PSP and a stronger perinuclear aggregates formation. We propose that these alterations contribute to the formation of a dysfunctional serinosome and thus to the observed reduction of L-serine, glycine and D-serine levels (the latter playing a crucial role in modulating NMDA receptors). The characterization of patients harbouring the Asn133Ser PSP substitution allows to go deep into the molecular mechanisms related to L-serine deficit and to suggest treatments to cope with the observed amino acids alterations.
    Keywords:  Genetic disease; Phosphorylated pathway; Serine deficiency; Structure–function relationships
    DOI:  https://doi.org/10.1038/s41598-024-63164-y
  18. Basic Clin Pharmacol Toxicol. 2024 May 27.
    Regulation of mitochondrial dysfunction by estrogens and estrogen receptors in Alzheimer's disease: A focused review.
    Shokouh Arjmand, Mehran Ilaghi, Ali Karimi Sisakht, Matti Bock Guldager, Gregers Wegener, Anne M Landau, Albert Gjedde.
      Alzheimer's disease (AD) is a neurodegenerative disorder that primarily manifests itself by progressive memory loss and cognitive decline, thus significantly affecting memory functions and quality of life. In this review, we proceed from the understanding that the canonical amyloid-β hypothesis, while significant, has faced setbacks, highlighting the need to adopt a broader perspective considering the intricate interplay of diverse pathological pathways for effective AD treatments. Sex differences in AD offer valuable insights into a better understanding of its pathophysiology. Fluctuation of the levels of ovarian sex hormones during perimenopause is associated with changes in glucose metabolism, as a possible window of opportunity to further understand the roles of sex steroid hormones and their associated receptors in the pathophysiology of AD. We review these dimensions, emphasizing the potential of estrogen receptors (ERs) to reveal mitochondrial functions in the search for further research and therapeutic strategies for AD pharmacotherapy. Understanding and addressing the intricate interactions of mitochondrial dysfunction and ERs potentially pave the way for more effective approaches to AD therapy.
    Keywords:  Alzheimer's disease; estrogen receptors; estrogens; glucose metabolism; mitochondrial bioenergetics; mitochondrial dynamics; mitochondrial estrogen receptor; mitochondrial function; sex differences
    DOI:  https://doi.org/10.1111/bcpt.14035
  19. Sci Adv. 2024 May 31. 10(22): eadj1431
    13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.
    Eric H Ma, Michael S Dahabieh, Lisa M DeCamp, Irem Kaymak, Susan M Kitchen-Goosen, Brandon M Oswald, Joseph Longo, Dominic G Roy, Mark J Verway, Radia M Johnson, Bozena Samborska, Lauren R Duimstra, Catherine A Scullion, Mya Steadman, Matthew Vos, Thomas P Roddy, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.
      Infusion of 13C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes-infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.
    DOI:  https://doi.org/10.1126/sciadv.adj1431
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