bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2023‒07‒30
twenty-one papers selected by
Regina F. Fernández
Johns Hopkins University
  1. Type-1 cannabinoid receptors and their ever-expanding roles in brain energy processes.
  2. Lactate metabolism in neurodegenerative diseases.
  3. Spatial lipidomics reveals brain region-specific changes of sulfatides in an experimental MPTP Parkinson's disease primate model.
  4. Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury.
  5. Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease: beyond the role of amyloid beta.
  6. mGluR5 in astrocytes in the ventromedial hypothalamus regulates PACAP neurons and glucose homeostasis.
  7. Adverse effects of gestational ω-3 and ω-6 polyunsaturated fatty acid imbalance on the programming of fetal brain development.
  8. Reexamining the Causes and Effects of Cholesterol Deposition in the Brains of Patients with Alzheimer's Disease.
  9. High-altitude cerebral hypoxia promotes mitochondrial dysfunction and apoptosis of mouse neurons.
  10. The impact of high-glucose or high-fat diets on the metabolomic profiling of mice.
  11. PLA2G2E-mediated lipid metabolism triggers brain-autonomous neural repair after ischemic stroke.
  12. Ketogenic diet and β-Hydroxybutyrate alleviate ischemic brain injury in mice via an IRAKM-dependent pathway.
  13. Sphingosine 1-Phosphate Lyase in the Developing and Injured Nervous System: a Dichotomy?
  14. L-carnitine and Acetyl-L Carnitine: A Possibility for Treating Alterations Induced by Obesity in the Central Nervous System.
  15. Mitochondrial Proteome Changes in Rett Syndrome.
  16. Synapse-specific defects in synaptic transmission in the cerebellum of W246G mutant ELOVL4 rats- a model of human SCA34.
  17. Molecular Understanding of ER-MT Communication Dysfunction during Neurodegeneration.
  18. Lipid-correlated alterations in the transcriptome are enriched in several specific pathways in the postmortem prefrontal cortex of Japanese patients with schizophrenia.
  19. White Matter Metabolite Ratios Predict Cognitive Outcome in Pediatric Traumatic Brain Injury.
  20. PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics.
  21. Lysophospholipids transport across blood-brain barrier in an in vitro reconstruction model.
  1. J Neurochem. 2023 Jul 28.
    Type-1 cannabinoid receptors and their ever-expanding roles in brain energy processes.
    Ignacio Fernández-Moncada, Rui S Rodrigues, Unai B Fundazuri, Luigi Bellocchio, Giovanni Marsicano.
      The brain requires large quantities of energy to sustain its functions. At the same time, the brain is isolated from the rest of the body, forcing this organ to develop strategies to control and fulfill its own energy needs. Likely based on these constraints, several brain-specific mechanisms emerged during evolution. For example, metabolically specialized cells are present in the brain, where intercellular metabolic cycles are organized to separate workload and optimize the use of energy. To orchestrate these strategies across time and space, several signaling pathways control the metabolism of brain cells. One of such controlling systems is the endocannabinoid system, whose main signaling hub in the brain is the type-1 cannabinoid (CB1 ) receptor. CB1 receptors govern a plethora of different processes in the brain, including cognitive function, emotional responses, or feeding behaviors. Classically, the mechanisms of action of CB1 receptors on brain function had been explained by its direct targeting of neuronal synaptic function. However, new discoveries have challenged this view. In this review, we will present and discuss recent data about how a small fraction of CB1 receptors associated to mitochondrial membranes (mtCB1 ), are able to exert a powerful control on brain functions and behavior. mtCB1 receptors impair mitochondrial functions both in neurons and astrocytes. In the latter cells, this effect is linked to an impairment of astrocyte glycolytic function, resulting in specific behavioral outputs. Finally, we will discuss the potential implications of (mt)CB1 expression on oligodendrocytes and microglia metabolic functions, with the aim to encourage interdisciplinary approaches to better understand the role of (mt)CB1 receptors in brain function and behavior.
    Keywords:  CB1 receptors; astrocytes; glucose; lactate; mitochondria; neurons
    DOI:  https://doi.org/10.1111/jnc.15922
  2. Neural Regen Res. 2024 Jan;19(1): 69-74
    Lactate metabolism in neurodegenerative diseases.
    Chaoguang Yang, Rui-Yuan Pan, Fangxia Guan, Zengqiang Yuan.
      Lactate, a byproduct of glycolysis, was thought to be a metabolic waste until the discovery of the Warburg effect. Lactate not only functions as a metabolic substrate to provide energy but can also function as a signaling molecule to modulate cellular functions under pathophysiological conditions. The Astrocyte-Neuron Lactate Shuttle has clarified that lactate plays a pivotal role in the central nervous system. Moreover, protein lactylation highlights the novel role of lactate in regulating transcription, cellular functions, and disease development. This review summarizes the recent advances in lactate metabolism and its role in neurodegenerative diseases, thus providing optimal perspectives for future research.
    Keywords:  Alzheimer’s disease; Astrocyte-Neuron Lactate Shuttle; Parkinson’s disease; brain; central nervous system; glucose metabolism; glycolysis; neuroinflammation; protein lactylation; signaling molecule
    DOI:  https://doi.org/10.4103/1673-5374.374142
  3. NPJ Parkinsons Dis. 2023 Jul 26. 9(1): 118
    Spatial lipidomics reveals brain region-specific changes of sulfatides in an experimental MPTP Parkinson's disease primate model.
    Ibrahim Kaya, Anna Nilsson, Dominika Luptáková, Yachao He, Theodosia Vallianatou, Patrik Bjärterot, Per Svenningsson, Erwan Bezard, Per E Andrén.
      Metabolism of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) to the neurotoxin MPP+ in the brain causes permanent Parkinson's disease-like symptoms by destroying dopaminergic neurons in the pars compacta of the substantia nigra in humans and non-human primates. However, the complete molecular pathology underlying MPTP-induced parkinsonism remains poorly understood. We used dual polarity matrix-assisted laser desorption/ionization mass spectrometry imaging to thoroughly image numerous glycerophospholipids and sphingolipids in coronal brain tissue sections of MPTP-lesioned and control non-human primate brains (Macaca mulatta). The results revealed specific distributions of several sulfatide lipid molecules based on chain-length, number of double bonds, and importantly, hydroxylation stage. More specifically, certain long-chain hydroxylated sulfatides with polyunsaturated chains in the molecular structure were depleted within motor-related brain regions in the MPTP-lesioned animals, e.g., external and internal segments of globus pallidus and substantia nigra pars reticulata. In contrast, certain long-chain non-hydroxylated sulfatides were found to be elevated within the same brain regions. These findings demonstrate region-specific dysregulation of sulfatide metabolism within the MPTP-lesioned macaque brain. The depletion of long-chain hydroxylated sulfatides in the MPTP-induced pathology indicates oxidative stress and oligodendrocyte/myelin damage within the pathologically relevant brain regions. Hence, the presented findings improve our current understanding of the molecular pathology of MPTP-induced parkinsonism within primate brains, and provide a basis for further research regarding the role of dysregulated sulfatide metabolism in PD.
    DOI:  https://doi.org/10.1038/s41531-023-00558-1
  4. Front Mol Neurosci. 2023 ;16 1224964
    Mechanism of PGC-1α-mediated mitochondrial biogenesis in cerebral ischemia-reperfusion injury.
    Ying Yuan, Yuan Tian, Hui Jiang, Luo-Yang Cai, Jie Song, Rui Peng, Xiao-Ming Zhang.
      Cerebral ischemia-reperfusion injury (CIRI) is a series of cascade reactions that occur after blood flow recanalization in the ischemic zone in patients with cerebral infarction, causing an imbalance in intracellular homeostasis through multiple pathologies such as increased oxygen free radicals, inflammatory response, calcium overload, and impaired energy metabolism, leading to mitochondrial dysfunction and ultimately apoptosis. Rescue of reversibly damaged neurons in the ischemic hemispheric zone is the key to saving brain infarction and reducing neurological deficits. Complex and active neurological functions are highly dependent on an adequate energy supply from mitochondria. Mitochondrial biogenesis (MB), a process that generates new functional mitochondria and restores normal mitochondrial function by replacing damaged mitochondria, is a major mechanism for maintaining intra-mitochondrial homeostasis and is involved in mitochondrial quality control to ameliorate mitochondrial dysfunction and thus protects against CIRI. The main regulator of MB is peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α), which improves mitochondrial function to protect against CIRI by activating its downstream nuclear respiratory factor 1 (NRF1) and mitochondrial transcription factor A (TFAM) to promote mitochondrial genome replication and transcription. This paper provides a theoretical reference for the treatment of neurological impairment caused by CIRI by discussing the mechanisms of mitochondrial biogenesis during cerebral ischemia-reperfusion injury.
    Keywords:  PGC-1α; apoptosis; cerebral ischemia–reperfusion injury; mitochondria; mitochondrial biogenesis
    DOI:  https://doi.org/10.3389/fnmol.2023.1224964
  5. Neural Regen Res. 2024 Jan;19(1): 80-83
    Impact of apolipoprotein E isoforms on sporadic Alzheimer's disease: beyond the role of amyloid beta.
    Madia Lozupone, Francesco Panza.
      The impact of apolipoprotein E (ApoE) isoforms on sporadic Alzheimer's disease has long been studied; however, the influences of apolipoprotein E gene (APOE) on healthy and pathological human brains are not fully understood. ApoE exists as three common isoforms (ApoE2, ApoE3, and ApoE4), which differ in two amino acid residues. Traditionally, ApoE binds cholesterol and phospholipids and ApoE isoforms display different affinities for their receptors, lipids transport and distribution in the brain and periphery. The role of ApoE in the human depends on ApoE isoforms, brain regions, aging, and neural injury. APOE ε4 is the strongest genetic risk factor for sporadic Alzheimer's disease, considering its role in influencing amyloid-beta metabolism. The exact mechanisms by which APOE gene variants may increase or decrease Alzheimer's disease risk are not fully understood, but APOE was also known to affect directly and indirectly tau-mediated neurodegeneration, lipids metabolism, neurovascular unit, and microglial function. Consistent with the biological function of ApoE, ApoE4 isoform significantly altered signaling pathways associated with cholesterol homeostasis, transport, and myelination. Also, the rare protective APOE variants confirm that ApoE plays an important role in Alzheimer's disease pathogenesis. The objectives of the present mini-review were to describe classical and new roles of various ApoE isoforms in Alzheimer's disease pathophysiology beyond the deposition of amyloid-beta and to establish a functional link between APOE, brain function, and memory, from a molecular to a clinical level. APOE genotype also exerted a heterogeneous effect on clinical Alzheimer's disease phenotype and its outcomes. Not only in learning and memory but also in neuropsychiatric symptoms that occur in a premorbid condition. Clarifying the relationships between Alzheimer's disease-related pathology with neuropsychiatric symptoms, particularly suicidal ideation in Alzheimer's disease patients, may be useful for elucidating also the underlying pathophysiological process and its prognosis. Also, the effects of anti-amyloid-beta drugs, recently approved for the treatment of Alzheimer's disease, could be influenced by the APOE genotype.
    Keywords:  Alzheimer’s disease; amyloid-beta; apolipoprotein E; dementia; glymphatic transport; lipids; neuropsychiatric symptoms; neurovascular unit; tau protein
    DOI:  https://doi.org/10.4103/1673-5374.375316
  6. J Neurosci. 2023 Jul 28. pii: JN-RM-0193-23. [Epub ahead of print]
    mGluR5 in astrocytes in the ventromedial hypothalamus regulates PACAP neurons and glucose homeostasis.
    Alice Meng, Dominique Ameroso, Maribel Rios.
      The ventromedial hypothalamus (VMH) is a functionally heterogeneous nucleus critical for systemic energy, glucose and lipid balance. We showed previously that the metabotropic glutamate receptor 5 (mGluR5) plays essential roles regulating excitatory and inhibitory transmission in SF1+ neurons of the VMH and facilitating glucose and lipid homeostasis in female mice. While mGluR5 is also highly expressed in VMH astrocytes in the mature brain, its role there influencing central metabolic circuits is unknown. In contrast to the glucose intolerance observed only in female mice lacking mGluR5 in VMH SF1 neurons, selective depletion of mGluR5 in VMH astrocytes enhanced glucose tolerance without affecting food intake or body weight in both adult female and male mice. The improved glucose tolerance was associated with elevated glucose-stimulated insulin release. Astrocytic mGluR5 male and female mutants also exhibited reduced adipocyte size and increased sympathetic tone in gonadal white adipose tissue. Diminished excitatory drive and synaptic inputs onto VMH PACAP+ neurons and reduced activity of these cells during acute hyperglycemia underlie the observed changes in glycemic control. These studies reveal an essential role of astrocytic mGluR5 in the VMH regulating the excitatory drive onto PACAP+ neurons and activity of these cells facilitating glucose homeostasis in male and female mice.Significance Statement:Neuronal circuits within the ventromedial hypothalamus (VMH) play chief roles in the regulation of whole-body metabolic homeostasis. It remains unclear how astrocytes influence neurotransmission in this region to facilitate energy and glucose balance control. Here, we explored the role of the metabotropic glutamate receptor, mGluR5, using a mouse model with selective depletion of mGluR5 from VMH astrocytes. We show that astrocytic mGluR5 critically regulates the excitatory drive and activity of PACAP-expressing neurons in the VMH to control glucose homeostasis in both female and male mice. Furthermore, mGluR5 in VMH astrocytes influences adipocyte size and sympathetic tone in white adipose tissue. These studies provide novel insight towards the importance of hypothalamic astrocytes participating in central circuits regulating peripheral metabolism.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0193-23.2023
  7. J Neuroendocrinol. 2023 Jul 05.
    Adverse effects of gestational ω-3 and ω-6 polyunsaturated fatty acid imbalance on the programming of fetal brain development.
    Valentina Cinquina, Erik Keimpema, Daniela D Pollak, Tibor Harkany.
      Obesity is a key medical challenge of our time. The increasing number of children born to overweight or obese women is alarming. During pregnancy, the circulation of the mother and her fetus interact to maintain the uninterrupted availability of essential nutrients for fetal organ development. In doing so, the mother's dietary preference determines the amount and composition of nutrients reaching the fetus. In particular, the availability of polyunsaturated fatty acids (PUFAs), chiefly their ω-3 and ω-6 subclasses, can change when pregnant women choose a specific diet. Here, we provide a succinct overview of PUFA biochemistry, including exchange routes between ω-3 and ω-6 PUFAs, the phenotypes, and probable neurodevelopmental disease associations of offspring born to mothers consuming specific PUFAs, and their mechanistic study in experimental models to typify signaling pathways, transcriptional, and epigenetic mechanisms by which PUFAs can imprint long-lasting modifications to brain structure and function. We emphasize that the ratio, rather than the amount of individual ω-3 or ω-6 PUFAs, might underpin physiologically correct cellular differentiation programs, be these for neurons or glia, during pregnancy. Thereupon, the PUFA-driven programming of the brain is contextualized for childhood obesity, metabolic, and endocrine illnesses.
    Keywords:  arachidonic acid; dietary requirement; neurodevelopmental disorder; neuronal wiring; nutrient conversion
    DOI:  https://doi.org/10.1111/jne.13320
  8. Mol Neurobiol. 2023 Jul 28.
    Reexamining the Causes and Effects of Cholesterol Deposition in the Brains of Patients with Alzheimer's Disease.
    Ze-Lin Hu, Yang-Qi Yuan, Zhen Tong, Mei-Qing Liao, Shun-Ling Yuan, Ye Jian, Jia-Lun Yang, Wen-Feng Liu.
      Alzheimer's disease (AD) is a degenerative disease of the central nervous system. Numerous studies have shown that imbalances in cholesterol homeostasis in the brains of AD patients precede the onset of clinical symptoms. In addition, cholesterol deposition has been observed in the brains of AD patients even though peripheral cholesterol does not enter the brain through the blood‒brain barrier (BBB). Studies have demonstrated that cholesterol metabolism in the brain is associated with many pathological conditions, such as amyloid beta (Aβ) production, Tau protein phosphorylation, oxidative stress, and inflammation. In 2022, some scholars put forward a new hypothesis of AD: the disease involves lipid invasion and its exacerbation of the abnormal metabolism of cholesterol in the brain. In this review, by discussing the latest research progress, the causes and effects of cholesterol retention in the brains of AD patients are analyzed and discussed. Additionally, the possible mechanism through which AD may be improved by targeting cholesterol is described. Finally, we propose that improving the impairments in cholesterol removal observed in the brains of AD patients, instead of further reducing the already impaired cholesterol synthesis in the brain, may be the key to preventing cholesterol deposition and improving the corresponding pathological symptoms.
    Keywords:  ABCA1; Alzheimer’s disease; Cholesterol; Oxysterols; Statins
    DOI:  https://doi.org/10.1007/s12035-023-03529-y
  9. Front Mol Neurosci. 2023 ;16 1216947
    High-altitude cerebral hypoxia promotes mitochondrial dysfunction and apoptosis of mouse neurons.
    Yu Huan, Huilin Quan, Bo Jia, Guangzhi Hao, Zuolin Shi, Tianzi Zhao, Ying Yuan, Fang Yuan, Yushu Dong, Guobiao Liang.
      Introduction: Neuronal cell death is an important factor in the pathogenesis of acute high-altitude cerebral hypoxia; however, the underlying molecular mechanism remains unclear. In this study, we tested if high-altitude hypoxia (HAH) causes neuronal death and mitochondrial dysfunction using various in vivo and in vitro approaches.Methods: Acute high-altitude cerebral hypoxia was induced by hypobaric hypoxia chamber in male mice. we explored the mechanisms of neuronal cell death using immunofluorescence, western blotting, transmission electron microscopy, and flow cytometry. Next, mitochondrial function and morphology were observed using Jc-1 staining, seahorse assay, western blotting, MitoTracker staining, and transmission electron microscopy. Moreover, open field test, elevated plus test, and Morris water maze were applied for animal behavior.
    Results: Results revealed that HAH disrupted mitochondrial function and promoted neuronal apoptosis and necroptosis both in HT-22 cells and in mouse hippocampal neurons. Moreover, the mitochondrial membrane potential and adenosine triphosphate production decreased in neurons after HAH, while oxidative stress and mitochondrial fission increased. Behavioral studies suggested that HAH induced anxiety-like behavior and impaired spatial memory, while it had no effect on athletic ability.
    Discussion: These findings demonstrated that HAH promotes mitochondrial dysfunction and apoptosis of mouse neurons, thus providing new insights into the role of mitochondrial function and neuronal cell death in acute high-altitude cerebral hypoxia.
    Keywords:  apoptosis; high-altitude hypoxia; mitochondrial fission; necroptosis; neurons
    DOI:  https://doi.org/10.3389/fnmol.2023.1216947
  10. Front Nutr. 2023 ;10 1171806
    The impact of high-glucose or high-fat diets on the metabolomic profiling of mice.
    Dadi Xie, Yanbo Zhang, Yujin Guo, Xianzhong Xue, Shiyuan Zhao, Chunmei Geng, Yuanyuan Li, Rui Yang, Yizhang Gan, Hanbing Li, Zhongfa Ren, Pei Jiang.
      Objective: Diets high in glucose or fat contribute to an increased prevalence of the diseases. Therefore, the objective of the current research was to observe and evaluate the impact of dietary components on different metabolomic profiles in primary tissues of mice.Methods: For 8 weeks, diet with high-glucose or-fat was given to C57BL/6 J mice. The levels of metabolites in the primary tissues of mice were studied using gas chromatography-mass spectrometry (GC-MS) and analyzed using multivariate statistics.
    Results: By comparing the metabolic profiles between the two diet groups and control group in mice main tissues, our study revealed 32 metabolites in the high-glucose diet (HGD) group and 28 metabolites in the high-fat diet (HFD) group. The most significantly altered metabolites were amino acids (AAs; L-alanine, L-valine, glycine, L-aspartic acid, L-isoleucine, L-leucine, L-threonine, L-glutamic acid, phenylalanine, tyrosine, serine, proline, and lysine), fatty acids (FAs; propanoic acid, 9,12-octadecadienoic acid, pentadecanoic acid, hexanoic acid, and myristic acid), and organic compounds (succinic acid, malic acid, citric acid, L-(+)-lactic acid, myo-inositol, and urea). These metabolites are implicated in many metabolic pathways related to energy, AAs, and lipids metabolism.
    Conclusion: We systematically analyzed the metabolic changes underlying high-glucose or high-fat diet. The two divergent diets induced patent changes in AA and lipid metabolism in the main tissues, and helped identify metabolic pathways in a mouse model.
    Keywords:  diet; gas chromatography-mass spectrometry; glucolipid; metabolome; tissue
    DOI:  https://doi.org/10.3389/fnut.2023.1171806
  11. Neuron. 2023 Jul 17. pii: S0896-6273(23)00483-X. [Epub ahead of print]
    PLA2G2E-mediated lipid metabolism triggers brain-autonomous neural repair after ischemic stroke.
    Akari Nakamura, Seiichiro Sakai, Yoshitaka Taketomi, Jun Tsuyama, Yoshimi Miki, Yuichiro Hara, Nobutaka Arai, Yuki Sugiura, Hideya Kawaji, Makoto Murakami, Takashi Shichita.
      The brain is generally resistant to regeneration after damage. The cerebral endogenous mechanisms triggering brain self-recovery have remained unclarified to date. We here discovered that the secreted phospholipase PLA2G2E from peri-infarct neurons generated dihomo-γ-linolenic acid (DGLA) as necessary for triggering brain-autonomous neural repair after ischemic brain injury. Pla2g2e deficiency diminished the expression of peptidyl arginine deiminase 4 (Padi4), a global transcriptional regulator in peri-infarct neurons. Single-cell RNA sequencing (scRNA-seq) and epigenetic analysis demonstrated that neuronal PADI4 had the potential for the transcriptional activation of genes associated with recovery processes after ischemic stroke through histone citrullination. Among various DGLA metabolites, we identified 15-hydroxy-eicosatrienoic acid (15-HETrE) as the cerebral metabolite that induced PADI4 in peri-infarct-surviving neurons. Administration of 15-HETrE enhanced functional recovery after ischemic stroke. Thus, our research clarifies the promising potential of brain-autonomous neural repair triggered by the specialized lipids that initiate self-recovery processes after brain injury.
    Keywords:  PADI4; histone citrullination; inflammation; ischemic stroke; lipidomics; neural repair; neuronal scRNA-seq; phospholipase; stroke recovery
    DOI:  https://doi.org/10.1016/j.neuron.2023.06.024
  12. Eur J Pharmacol. 2023 Jul 20. pii: S0014-2999(23)00445-4. [Epub ahead of print]955 175933
    Ketogenic diet and β-Hydroxybutyrate alleviate ischemic brain injury in mice via an IRAKM-dependent pathway.
    Chuman Lin, Shengnan Wang, Jiaxin Xie, Juan Zhu, Jiawei Xu, Kewei Liu, Jiancong Chen, Mingjia Yu, Hengren Zhong, Kaibin Huang, Suyue Pan.
      Ketogenic diet (KD) is a classical nonpharmacological therapy that has recently been shown to benefit cerebral ischemia, but the mechanism remains unclear. This study investigated the neuroprotective effects of KD pretreatment and β-hydroxybutyrate (BHB, bioactive product of KD) post-treatment in a mouse model of temporary middle cerebral artery occlusion (tMCAO). Neurological function, infarct volume, as well as inflammatory reactions are evaluated 24 h after ischemia. Results showed that both KD pretreatment or BHB post-treatment improved the Bederson score and Grip test score, reduced infarct volume and the extravasation of IgG, suppressed the over-activation of microglia, and modulated the expression of cytokines. Mechanically, we found that both KD pretreatment or BHB post-treatment significantly stimulated the expression of interleukin-1 receptor-associated kinase M (IRAKM) and then inhibited the nuclear translocation of NF-κB. IRAKM deletion (Irakm-/-) exacerbated tMCAO-induced neurovascular injuries, and aggravated neuroinflammatory response. Moreover, KD pretreatment or BHB post-treatment lost their neuroprotection in the tMCAO-treated Irakm-/- mice. Our results support that KD pretreatment and BHB post-treatment alleviate ischemic brain injury in mice, possibly via an IRAKM-dependent way.
    Keywords:  IRAKM; Ischemic brain injury; Ketogenic diet; Proinflammatory cytokines; β-Hydroxybutyrate
    DOI:  https://doi.org/10.1016/j.ejphar.2023.175933
  13. Mol Neurobiol. 2023 Jul 28.
    Sphingosine 1-Phosphate Lyase in the Developing and Injured Nervous System: a Dichotomy?
    Junhua Xiao.
      Sphingosine 1-phosphate lyase (SPL) is the terminal enzyme that controls the degradation of the bioactive lipid sphingosine 1-phosphate (S1P) within an interconnected sphingolipid metabolic network. The unique metabolic position of SPL in maintaining S1P levels implies SPL could be an emerging new therapeutic target. Over the past decade, an evolving effort has been made to unravel the role of SPL in the nervous system; however, to what extent SPL influences the developing and mature nervous system through altering S1P biosynthesis remains opaque. While congenital SPL deletion is associated with deficits in the developing nervous system, the loss of SPL activity in adults appears to be neuroprotective in acquired neurological disorders. The controversial findings concerning SPL's role in the nervous system are further constrained by the current genetic and pharmacological tools. This review attempts to focus on the multi-faceted nature of SPL function in the mammalian nervous systems, implying its dichotomy in the developing and adult central nervous system (CNS). This article also highlights SPL is emerging as a therapeutic molecule that can be selectively targeted to modulate S1P for the treatment of acquired neurodegenerative diseases, raising new questions for future investigation. The development of cell-specific inducible conditional SPL mutants and selective pharmacological tools will allow the precise understanding of SPL's function in the adult CNS, which will aid the development of a new strategy focusing on S1P-based therapies for neuroprotection.
    Keywords:  Astrocyte; Glial cells; Microglia; Multiple sclerosis; Neuron; Sphingosine 1-phosphate; Sphingosine 1-phosphate lyase
    DOI:  https://doi.org/10.1007/s12035-023-03524-3
  14. Neurochem Res. 2023 Jul 27.
    L-carnitine and Acetyl-L Carnitine: A Possibility for Treating Alterations Induced by Obesity in the Central Nervous System.
    Larissa Espindola da Silva, Mariana Pacheco de Oliveira, Mariella Reinol da Silva, Jéssica da Silva Abel, Gisele Tartari, Maiara de Aguiar da Costa, Cinara Ludvig Gonçalves, Gislaine Tezza Rezin.
      Excessive consumption of nutrients, as well as obesity, leads to an inflammatory process, especially in adipose tissue. This inflammation reaches the systemic level and, subsequently, the central nervous system (CNS), which can lead to oxidative stress and mitochondrial dysfunction, resulting in brain damage. Thus, adequate treatment for obesity is necessary, including lifestyle changes (diet adequation and physical activity) and pharmacotherapy. However, these drugs can adversely affect the individual's health. In this sense, searching for new therapeutic alternatives for reestablishing metabolic homeostasis is necessary. L-carnitine (LC) and acetyl-L-carnitine (LAC) have neuroprotective effects against oxidative stress and mitochondrial dysfunction in several conditions, including obesity. Therefore, this study aimed to conduct a narrative review of the literature on the effect of LC and LAC on brain damage caused by obesity, in particular, on mitochondrial dysfunction and oxidative stress. Overall, these findings highlight that LC and LAC may be a promising treatment for recovering REDOX status and mitochondrial dysfunction in the CNS in obesity. Future work should focus on better elucidating the molecular mechanisms behind this treatment.
    Keywords:  Acetylcarnitine; Brain; Obesity; Oxidative stress carnitine
    DOI:  https://doi.org/10.1007/s11064-023-04000-z
  15. Biology (Basel). 2023 Jul 03. pii: 956. [Epub ahead of print]12(7):
    Mitochondrial Proteome Changes in Rett Syndrome.
    Gocha Golubiani, Laura van Agen, Lia Tsverava, Revaz Solomonia, Michael Müller.
      Rett syndrome (RTT) is a genetic neurodevelopmental disorder with mutations in the X-chromosomal MECP2 (methyl-CpG-binding protein 2) gene. Most patients are young girls. For 7-18 months after birth, they hardly present any symptoms; later they develop mental problems, a lack of communication, irregular sleep and breathing, motor dysfunction, hand stereotypies, and seizures. The complex pathology involves mitochondrial structure and function. Mecp2-/y hippocampal astrocytes show increased mitochondrial contents. Neurons and glia suffer from oxidative stress, a lack of ATP, and increased hypoxia vulnerability. This spectrum of changes demands comprehensive molecular studies of mitochondria to further define their pathogenic role in RTT. Therefore, we applied a comparative proteomic approach for the first time to study the entity of mitochondrial proteins in a mouse model of RTT. In the neocortex and hippocampus of symptomatic male mice, two-dimensional gel electrophoresis and subsequent mass-spectrometry identified various differentially expressed mitochondrial proteins, including components of respiratory chain complexes I and III and the ATP-synthase FoF1 complex. The NADH-ubiquinone oxidoreductase 75 kDa subunit, NADH dehydrogenase [ubiquinone] iron-sulfur protein 8, NADH dehydrogenase [ubiquinone] flavoprotein 2, cytochrome b-c1 complex subunit 1, and ATP synthase subunit d are upregulated either in the hippocampus alone or both the hippocampus and neocortex of Mecp2-/y mice. Furthermore, the regulatory mitochondrial proteins mitofusin-1, HSP60, and 14-3-3 protein theta are decreased in the Mecp2-/y neocortex. The expressional changes identified provide further details of the altered mitochondrial function and morphology in RTT. They emphasize brain-region-specific alterations of the mitochondrial proteome and support the notion of a metabolic component of this devastating disorder.
    Keywords:  Mecp2; Rett syndrome; hippocampus; mitochondria; mouse model; neocortex; proteomics
    DOI:  https://doi.org/10.3390/biology12070956
  16. J Neurosci. 2023 Jul 25. pii: JN-RM-0378-23. [Epub ahead of print]
    Synapse-specific defects in synaptic transmission in the cerebellum of W246G mutant ELOVL4 rats- a model of human SCA34.
    Raghavendra Y Nagaraja, Megan A Stiles, David M Sherry, Martin-Paul Agbaga, Mohiuddin Ahmad.
      Elongation of Very Long Fatty Acids-4 (ELOVL4) mediates biosynthesis of Very Long Chain-Fatty Acids (VLC-FA; ≥28 carbons). Various mutations in this enzyme result in spinocerebellar ataxia-34 (SCA34). We generated a rat model of human SCA34 by knock-in of a naturally occurring c.736T>G, p.W246G mutation in the Elovl4 gene. Our previous analysis of homozygous W246G mutant ELOVL4 rats (MUT) revealed early-onset gait disturbance and impaired synaptic transmission and plasticity at parallel fiber-to-Purkinje cell (PF-PC) and climbing fiber-to-Purkinje cell (CF-PC) synapses. However, the underlying mechanisms that caused these defects remained unknown. Here, we report detailed patch-clamp recordings from Purkinje cells that identify impaired synaptic mechanisms. Our results show that miniature Excitatory Postsynaptic Current (mEPSC) frequency is reduced in MUT rats with no change in mEPSC amplitude, suggesting a presynaptic defect of excitatory synaptic transmission on Purkinje cells. We also find alterations in inhibitory synaptic transmission as miniature Inhibitory Postsynaptic Current (mIPSC) frequency and amplitude are increased in MUT Purkinje cells. Paired-pulse ratio is reduced at PF-PC synapses but increased at CF-PC synapses in MUT rats, which along with results from high frequency stimulation suggest opposite changes in the release probability at these two synapses. In contrast, we identify exaggerated persistence of EPSC amplitude at CF-PC and PF-PC synapses in MUT cerebellum, suggesting a larger readily releasable pool at both synapses. Furthermore, the dendritic spine density is reduced in MUT Purkinje cells. Thus, our results uncover novel mechanisms of action of VLC-FA at cerebellar synapses, and elucidate the synaptic dysfunction underlying SCA34 pathology.SIGNIFICANCE STATEMENTVery Long Chain-Fatty Acids (VLC-FA) are an understudied class of fatty acids that are present in the brain. They are critical for brain function as their deficiency caused by mutations in ELOVL4, the enzyme that mediates their biosynthesis, results in neurological diseases including spinocerebellar ataxia-34 (SCA34), neuroichthyosis, and Stargardt-like macular dystrophy. In this study, we investigated the synaptic defects present in a rat model of SCA34 and identified defects in presynaptic neurotransmitter release and dendritic spine density at synapses in the cerebellum, a brain region involved in motor coordination. These results advance our understanding of the synaptic mechanisms regulated by VLC-FA and describe the synaptic dysfunction that leads to motor incoordination in SCA34.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0378-23.2023
  17. Mitochondrion. 2023 Jul 24. pii: S1567-7249(23)00068-5. [Epub ahead of print]
    Molecular Understanding of ER-MT Communication Dysfunction during Neurodegeneration.
    Shivkumar S Sammeta, Trupti A Banarase, Sandip R Rahangdale, Nitu L Wankhede, Manish M Aglawe, Brijesh G Taksande, Shubhada V Mangrulkar, Aman B Upaganlawar, Sushruta Koppula, Spandana Rajendra Kopalli, Milind J Umekar, Mayur B Kale.
      Biological researchers are seeing organelles in a new light. These cellular entities have been believed to be singular and distinctive structures that performed specialized purposes for a very long time. But in recentpast years, scientists have learned that organelles become dynamic and make physical contact. Additionally, Biological processes are regulated by organelles interactions and its alteration play an important role in cell malfunctioning and several pathologies, including neurodegenerative diseases. Mitochondrial-ER contact sites (MERCS) have received considerable attention in the domain of cell homeostasis and dysfunction, specifically in the area of neurodegeneration. This is largely due to the significant role of this subcellular compartment in a diverse array of vital cellular functions, including Ca2+ homeostasis, transport, bioenergetics and turnover, mitochondrial dynamics, apoptotic signaling, ER stress, and inflammation. A significant number of disease-associated proteins were found to physically interact with the ER-Mitochondria (ER-MT) interface, causing structural and/or functional alterations in this compartment. In this review, we summarize current knowledge about the structure and functions of the ER-MT contact sites, as well as the possible repercussions of their alteration in notable neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and fronto-temporal dementia. The constraints and complexities in defining the nature and origin of the highlighted defects in ER-MT communication, as well as their concise contribution to the neurodegenerative process, are illustrated in particular. The possibility of using MERCS as a potential drug target to prevent neuronal damage and ultimately neurodegeneration is the topic of our final discussion.
    Keywords:  Alzheimer’s disease; Amyotrophic lateral sclerosis; Mitochondria–ER contact sites (MERCS); Parkinson’s disease; mitochondria–ER-associated membrane (MAM); neurodegeneration
    DOI:  https://doi.org/10.1016/j.mito.2023.07.005
  18. Neuropsychopharmacol Rep. 2023 Jul 27.
    Lipid-correlated alterations in the transcriptome are enriched in several specific pathways in the postmortem prefrontal cortex of Japanese patients with schizophrenia.
    Wataru Arihisa, Takeshi Kondo, Katsushi Yamaguchi, Junya Matsumoto, Hiroki Nakanishi, Yasuto Kunii, Hiroyasu Akatsu, Mizuki Hino, Yoshio Hashizume, Shumpei Sato, Shinji Sato, Shin-Ichi Niwa, Hirooki Yabe, Takehiko Sasaki, Shuji Shigenobu, Mitsutoshi Setou.
      AIMS: Schizophrenia is a chronic relapsing psychiatric disorder that is characterized by many symptoms and has a high heritability. There were studies showing that the phospholipid abnormalities in subjects with schizophrenia (Front Biosci, S3, 2011, 153; Schizophr Bull, 48, 2022, 1125; Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933). Disturbances in prefrontal cortex phospholipid and fatty acid composition have been reported in subjects with schizophrenia (Sci Rep, 7, 2017, 6; Anal Bioanal Chem, 400, 2011, 1933; Schizophr Res, 215, 2020, 493; J Psychiatr Res, 47, 2013, 636; Int J Mol Sci, 22, 2021). For exploring the signaling pathways contributing to the lipid changes in previous study (Sci Rep, 7, 2017, 6), we performed two types of transcriptome analyses in subjects with schizophrenia: an unbiased transcriptome analysis solely based on RNA-seq data and a correlation analysis between levels of gene expression and lipids.METHODS: RNA-Seq analysis was performed in the postmortem prefrontal cortex from 10 subjects with schizophrenia and 5 controls. Correlation analysis between the transcriptome and lipidome from 9 subjects, which are the same samples in the previous lipidomics study (Sci Rep, 7, 2017, 6).
    RESULTS: Extraction of differentially expressed genes (DEGs) and further sequence and functional group analysis revealed changes in gene expression levels in phosphoinositide 3-kinase (PI3K)-Akt signaling and the complement system. In addition, a correlation analysis clarified alterations in ether lipid metabolism pathway, which is not found as DEGs in transcriptome analysis alone.
    CONCLUSIONS: This study provided results of the integrated analysis of the schizophrenia-associated transcriptome and lipidome within the PFC and revealed that lipid-correlated alterations in the transcriptome are enriched in specific pathways including ether lipid metabolism pathway.
    Keywords:  lipidomics; postmortem brain; schizophrenia; transcriptomics
    DOI:  https://doi.org/10.1002/npr2.12368
  19. Metabolites. 2023 Jun 22. pii: 778. [Epub ahead of print]13(7):
    White Matter Metabolite Ratios Predict Cognitive Outcome in Pediatric Traumatic Brain Injury.
    Luke Berger, Barbara Holshouser, Joy G Nichols, Jamie Pivonka-Jones, Stephen Ashwal, Brenda Bartnik-Olson.
      The prognostic ability of global white matter and gray matter metabolite ratios following pediatric traumatic brain injury (TBI) and their relationship to 12-month neuropsychological assessments of intelligence quotient (IQ), attention, and memory is presented. Three-dimensional proton magnetic resonance spectroscopic imaging (MRSI) in pediatric subjects with complicated mild (cMild), moderate, and severe TBI was acquired acutely (6-18 days) and 12 months post-injury and compared to age-matched typically developing adolescents. A global linear regression model, co-registering MRSI metabolite maps with 3D high-resolution magnetic resonance images, was used to identify longitudinal white matter and gray matter metabolite ratio changes. Acutely, gray matter NAA/Cr, white matter NAA/Cr, and white matter NAA/Cho ratios were significantly lower in TBI groups compared to controls. Gray matter NAA/Cho was reduced only in the severe TBI group. At 12 months, all metabolite ratios normalized to control levels in each of the TBI groups. Acute gray matter and white matter NAA ratios were significantly correlated to 12-month assessments of IQ, attention, and memory. These findings suggest that whole brain gray matter and white matter metabolite ratios reflect longitudinal changes in neuronal metabolism following TBI, which can be used to predict neuropsychological outcomes in pediatric subjects.
    Keywords:  global linear regression; magnetic resonance spectroscopy; pediatric; tissue segmentation; traumatic brain injury
    DOI:  https://doi.org/10.3390/metabo13070778
  20. Cell Rep. 2023 Jul 26. pii: S2211-1247(23)00906-3. [Epub ahead of print]42(8): 112895
    PGAM5 is an MFN2 phosphatase that plays an essential role in the regulation of mitochondrial dynamics.
    Sudeshna Nag, Kaitlin Szederkenyi, Olena Gorbenko, Hannah Tyrrell, Christopher M Yip, G Angus McQuibban.
      Mitochondrial morphology is regulated by the post-translational modifications of the dynamin family GTPase proteins including mitofusin 1 (MFN1), MFN2, and dynamin-related protein 1 (DRP1). Mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) is emerging as a regulator of these post-translational modifications; however, its precise role in the regulation of mitochondrial morphology is unknown. We show that PGAM5 interacts with MFN2 and DRP1 in a stress-sensitive manner. PGAM5 regulates MFN2 phosphorylation and consequently protects it from ubiquitination and degradation. Further, phosphorylation and dephosphorylation modification of MFN2 regulates its fusion ability. Phosphorylation enhances fission and degradation, whereas dephosphorylation enhances fusion. PGAM5 dephosphorylates MFN2 to promote mitochondrial network formation. Further, using a Drosophila genetic model, we demonstrate that the MFN2 homolog Marf and dPGAM5 are in the same biological pathway. Our results identify MFN2 dephosphorylation as a regulator of mitochondrial fusion and PGAM5 as an MFN2 phosphatase.
    Keywords:  CP: Molecular biology; DRP1; MFN2; PGAM5; mitochondrial morphology
    DOI:  https://doi.org/10.1016/j.celrep.2023.112895
  21. Biochem Biophys Res Commun. 2023 Jul 22. pii: S0006-291X(23)00910-5. [Epub ahead of print]676 91-96
    Lysophospholipids transport across blood-brain barrier in an in vitro reconstruction model.
    Tamotsu Tsukahara, Masanori Sasaki, Hisao Haniu, Yoshikazu Matsuda.
      This study builds on our previous study, which highlighted the need for further research on the potential use of lysophospholipid (LPL) supplementation to prevent chronic and age-related diseases. We aimed to evaluate the transmembrane transport of LPL across rat and monkey blood-brain barrier (BBB) models. An in vitro monkey BBB model is required to elucidate the differences between rat and primate BBB-related data and to measure the permeability of LPLs being researched in relation to the human BBB. Based on our previous experiment, porcine liver decomposition product-derived phospholipids (PEL) strongly inhibit α-synuclein (α-Syn) aggregation. We have identified several candidates potentially relevant for the inhibition of α-Syn aggregation, such as LPC18:1, LPE18:1, and LPI18:0; however, the BBB permeability of these LPLs remains unclear. In the present study, we assessed the ability of these LPLs to pass through the in vitro rat and monkey BBB models. LPC18:1 showed high BBB permeability, LPI18:0 showed medium permeability, and the BBB permeation of LPE18:1 was negligible. Our results suggest that LPC18:1 and LPI18:0 are functional food factors that can cross the BBB.
    Keywords:  Blood-brain barrier; Lysophospholipid; Transmembrane transport; α-Syn aggregation
    DOI:  https://doi.org/10.1016/j.bbrc.2023.07.044
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