bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2023–10–22
seventeen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. Stable isotope tracing reveals disturbed cellular energy and glutamate metabolism in hippocampal slices of aged male mice.
  2. An early glycolysis burst in microglia regulates mitochondrial dysfunction in oligodendrocytes under neuroinflammation.
  3. Metabolic remodeling in astrocytes: Paving the path to brain tumor development.
  4. Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease.
  5. Disturbance of mitochondrial functions caused by N-acetylglutamate and N-acetylmethionine in brain of adolescent rats: Potential relevance in aminoacylase 1 deficiency.
  6. Downregulation of the glucose transporter GLUT 1 in the cerebral microvasculature contributes to postoperative neurocognitive disorders in aged mice.
  7. Maternal DHA intake in mice increased DHA metabolites in the pup brain and ameliorated MeHg-induced behavioral disorder.
  8. Succinylation modification: a potential therapeutic target in stroke.
  9. Autophagy in neuroinflammation after traumatic brain injury.
  10. Modulation of Cellular Levels of Adenosine Phosphates and Creatine Phosphate in Cultured Primary Astrocytes.
  11. Is creatine a CNS neurotransmitter?
  12. Evaluation of Mitochondrial Function on Pyruvate Dehydrogenase Complex Deficient Patient-derived Cell Lines.
  13. Abnormal microglial density and morphology in the brain of cyclooxygenase 2 knockin mice.
  14. Control of mitochondrial dynamics by a fusogenic lipid.
  15. Descending GABAergic pathway links brain sugar-sensing to peripheral nociceptive gating in Drosophila.
  16. Region-specific mouse brain ganglioside distribution revealed by an improved isobaric aminoxyTMT labeling strategy with automated data processing.
  17. Role of rafts in neurological disorders.
  1. Neurochem Int. 2023 Oct 12. pii: S0197-0186(23)00154-7. [Epub ahead of print]171 105626
    Stable isotope tracing reveals disturbed cellular energy and glutamate metabolism in hippocampal slices of aged male mice.
    Laura Mikél McNair, Jens Velde Andersen, Helle Sønderby Waagepetersen.
      Neurons and astrocytes work in close metabolic collaboration, linking neurotransmission to brain energy and neurotransmitter metabolism. Dysregulated energy metabolism is a hallmark of the aging brain and may underlie the progressive age-dependent cognitive decline. However, astrocyte and neurotransmitter metabolism remains understudied in aging brain research. In particular, how aging affects metabolism of glutamate, being the primary excitatory neurotransmitter, is still poorly understood. Here we investigated critical aspects of cellular energy metabolism in the aging male mouse hippocampus using stable isotope tracing in vitro. Metabolism of [U-13C]glucose demonstrated an elevated glycolytic capacity of aged hippocampal slices, whereas oxidative [U-13C]glucose metabolism in the TCA cycle was significantly reduced with aging. In addition, metabolism of [1,2-13C]acetate, reflecting astrocyte energy metabolism, was likewise reduced in the hippocampal slices of old mice. In contrast, uptake and subsequent metabolism of [U-13C]glutamate was elevated, suggesting increased capacity for cellular glutamate handling with aging. Finally, metabolism of [15N]glutamate was maintained in the aged slices, demonstrating sustained glutamate nitrogen metabolism. Collectively, this study reveals fundamental alterations in cellular energy and neurotransmitter metabolism in the aging brain, which may contribute to age-related hippocampal deficits.
    Keywords:  Astrocytes; Glutamate uptake; Glutamate-glutamine cycle; Isotope tracing
    DOI:  https://doi.org/10.1016/j.neuint.2023.105626
  2. iScience. 2023 Oct 20. 26(10): 107921
    An early glycolysis burst in microglia regulates mitochondrial dysfunction in oligodendrocytes under neuroinflammation.
    Hamid Suhail, Mohammad Nematullah, Faraz Rashid, Mir Sajad, Mena Fatma, Jaspreet Singh, Insha Zahoor, Wing Lee Cheung, Nivedita Tiwari, Kameshwar Ayasolla, Ashok Kumar, Nasrul Hoda, Ramandeep Rattan, Shailendra Giri.
      Metabolism and energy processes governing oligodendrocyte function during neuroinflammatory disease are of great interest. However, how varied cellular environments affect oligodendrocyte activity during neuroinflammation is unknown. We demonstrate that activated microglial energy metabolism controls oligodendrocyte mitochondrial respiration and activity. Lipopolysaccharide/interferon gamma promote glycolysis and decrease mitochondrial respiration and myelin protein synthesis in rat brain glial cells. Enriched microglia showed an early burst in glycolysis. In microglia-conditioned medium, oligodendrocytes did not respire and expressed less myelin. SCENITH revealed metabolic derangement in microglia and O4-positive oligodendrocytes in endotoxemia and experimental autoimmune encephalitogenic models. The early burst of glycolysis in microglia was mediated by PDPK1 and protein kinase B/AKT signaling. We found that microglia-produced NO and itaconate, a tricarboxylic acid bifurcated metabolite, reduced mitochondrial respiration in oligodendrocytes. During inflammation, we discovered a signaling pathway in microglia that could be used as a therapeutic target to restore mitochondrial function in oligodendrocytes and induce remyelination.
    Keywords:  Cellular neuroscience; Immune response; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2023.107921
  3. Neurobiol Dis. 2023 Oct 13. pii: S0969-9961(23)00343-1. [Epub ahead of print] 106327
    Metabolic remodeling in astrocytes: Paving the path to brain tumor development.
    Myriam Jaraíz-Rodríguez, Lucia Del Prado, Eduardo Balsa.
      The brain is a highly metabolic organ, composed of multiple cell classes, that controls crucial functions of the body. Although neurons have traditionally been the main protagonist, astrocytes have gained significant attention over the last decade. In this regard, astrocytes are a type of glial cells that have recently emerged as critical regulators of central nervous system (CNS) function and play a significant role in maintaining brain energy metabolism. However, in certain scenarios, astrocyte behavior can go awry, which poses a significant threat to brain integrity and function. This is definitively the case for mutations that turn normal astrocytes and astrocytic precursors into gliomas, an aggressive type of brain tumor. In addition, healthy astrocytes can interact with tumor cells, becoming part of the tumor microenvironment and influencing disease progression. In this review, we discuss the recent evidence suggesting that disturbed metabolism in astrocytes can contribute to the development and progression of fatal human diseases such as cancer. Emphasis is placed on detailing the molecular bases and metabolic pathways of this disease and highlighting unique metabolic vulnerabilities that can potentially be exploited to develop successful therapeutic opportunities.
    Keywords:  Astrocytes; Astrocytoma; Cancer; Glioma; Metabolism
    DOI:  https://doi.org/10.1016/j.nbd.2023.106327
  4. Nat Immunol. 2023 Oct 19.
    Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease.
    Chia-Chen Liu, Na Wang, Yuanxin Chen, Yasuteru Inoue, Francis Shue, Yingxue Ren, Minghui Wang, Wenhui Qiao, Tadafumi C Ikezu, Zonghua Li, Jing Zhao, Yuka Martens, Sydney V Doss, Cassandra L Rosenberg, Suren Jeevaratnam, Lin Jia, Ana-Caroline Raulin, Fangfang Qi, Yiyang Zhu, Alla Alnobani, Joshua Knight, Yixing Chen, Cynthia Linares, Aishe Kurti, John D Fryer, Bin Zhang, Long-Jun Wu, Betty Y S Kim, Guojun Bu.
      Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.
    DOI:  https://doi.org/10.1038/s41590-023-01640-9
  5. Neurochem Int. 2023 Oct 16. pii: S0197-0186(23)00159-6. [Epub ahead of print] 105631
    Disturbance of mitochondrial functions caused by N-acetylglutamate and N-acetylmethionine in brain of adolescent rats: Potential relevance in aminoacylase 1 deficiency.
    Vanessa Trindade Bortoluzzi, Rafael Teixeira Ribeiro, Ângela Beatris Zemniaçak, Sâmela de Azevedo Cunha, Jörn Oliver Sass, Roger Frigério Castilho, Alexandre Umpierrez Amaral, Moacir Wajner.
      Aminoacylase 1 (ACY1) deficiency is a rare genetic disorder that affects the breakdown of short-chain aliphatic N-acetylated amino acids, leading to the accumulation of these amino acid derivatives in the urine of patients. Some of the affected individuals have presented with heterogeneous neurological symptoms such as psychomotor delay, seizures, and intellectual disability. Considering that the pathological mechanisms of brain damage in this disorder remain mostly unknown, here we investigated whether major metabolites accumulating in ACY1 deficiency, namely N-acetylglutamate (NAG) and N-acetylmethionine (NAM), could be toxic to the brain by examining their in vitro effects on important mitochondrial properties. We assessed the effects of NAG and NAM on membrane potential, swelling, reducing equivalents, and Ca2+ retention capacity in purified mitochondrial preparations obtained from the brain of adolescent rats. NAG and NAM decreased mitochondrial membrane potential, reducing equivalents, and calcium retention capacity, and induced swelling in Ca2+-loaded brain mitochondria supported by glutamate plus malate. Notably, these changes were completely prevented by the classical inhibitors of mitochondrial permeability transition (MPT) pore cyclosporin A plus ADP and by ruthenium red, implying the participation of MPT and Ca2+ in these effects. Our findings suggest that NAG- and NAM-induced disruption of mitochondrial functions involving MPT may represent relevant mechanisms of neuropathology in ACY1 deficiency.
    Keywords:  Aminoacylase 1 deficiency; Brain; Mitochondrial functions; Mitochondrial permeability transition; N-acetylglutamate; N-acetylmethionine
    DOI:  https://doi.org/10.1016/j.neuint.2023.105631
  6. J Neuroinflammation. 2023 Oct 19. 20(1): 237
    Downregulation of the glucose transporter GLUT 1 in the cerebral microvasculature contributes to postoperative neurocognitive disorders in aged mice.
    Ying Chen, Jin Joo, John Man-Tak Chu, Raymond Chuen-Chung Chang, Gordon Tin-Chun Wong.
       INTRODUCTION: Glucose transporter 1 (GLUT1) is essential for glucose transport into the brain and is predominantly expressed in the cerebral microvasculature. Downregulation of GLUT1 precedes the development of cognitive impairment in neurodegenerative conditions. Surgical trauma induces blood-brain barrier (BBB) disruption, neuroinflammation, neuronal mitochondria dysfunction, and acute cognitive impairment. We hypothesized that surgery reduces the expression of GLUT1 in the BBB that in turn disrupts its integrity and contributes to metabolic dysregulation in the brain that culminates in postoperative cognitive impairment.
    METHODOLOGY: Using an abdominal surgery model in aged WT mice, we assessed the perioperative changes in cognitive performance, tight junction proteins expression, GLUT1 expression, and the associated metabolic effects in the hippocampus. Thereafter, we evaluated the effects of these parameters in aged mice with conditional overexpression of GLUT1, and then again in aged mice with conditional overexpression of GLUT1 with or without prior exposure to the GLUT1 inhibitor ST-31.
    RESULTS: We showed a significant decline in cognitive performance, along with GLUT1 reduction and diminished glucose metabolism, especially in the ATP level in the postoperative mice compared with controls. Overexpression of GLUT1 expression alleviated postoperative cognitive decline and improved metabolic profiles, especially in adenosine, but did not directly restore ATP generation to control levels. GLUT1 inhibition ameliorated the postoperative beneficial effects of GLUT1 overexpression.
    CONCLUSIONS: Surgery-induced GLUT1 reduction significantly contributes to postoperative cognitive deficits in aged mice by affecting glucose metabolism in the brain. It indicates the potential of targeting GLUT1 to ameliorate perioperative neurocognitive disorders.
    Keywords:  Aging; Blood–brain barrier; GLUT1; Glucose metabolism; Postoperative neurocognitive disorders
    DOI:  https://doi.org/10.1186/s12974-023-02905-8
  7. J Lipid Res. 2023 Oct 12. pii: S0022-2275(23)00131-1. [Epub ahead of print] 100458
    Maternal DHA intake in mice increased DHA metabolites in the pup brain and ameliorated MeHg-induced behavioral disorder.
    Ami Oguro, Taichi Fujiyama, Yasuhiro Ishihara, Chisato Kataoka, Megumi Yamamoto, Komyo Eto, Yoshihiro Komohara, Susumu Imaoka, Toshihide Sakuragi, Mayumi Tsuji, Eiji Shibata, Yaichiro Kotake, Takeshi Yamazaki.
      Although pregnant women's fish consumption is beneficial for the brain development of the fetus due to the docosahexaenoic acid (DHA) in fish, seafood also contains methylmercury (MeHg), which adversely affects fetal brain development. Epidemiological studies suggest that high DHA levels in pregnant women's sera may protect the fetal brain from MeHg-induced neurotoxicity, but the underlying mechanism is unknown. Our earlier study revealed that DHA and its metabolite 19,20-dihydroxydocosapentaenoic acid (19,20-DHDP) produced by cytochrome P450s (P450s) and soluble epoxide hydrolase (sEH) can suppress MeHg-induced cytotoxicity in mouse primary neuronal cells. In the present study, DHA supplementation to pregnant mice suppressed MeHg-induced impairments of pups' body weight, grip strength, motor function, and short-term memory. DHA supplementation also suppressed MeHg-induced oxidative stress and the decrease in the number of subplate neurons in the cerebral cortex of the pups. DHA supplementation to dams significantly increased the DHA metabolites 19,20- epoxydocosapentaenoic acid (19,20-EDP) and 19,20-DHDP as well as DHA itself in the fetal and infant brains, although the expression levels of P450s and sEH were low in the fetal brain and liver. DHA metabolites were detected in the mouse breast milk and in human umbilical cord blood, indicating the active transfer of DHA metabolites from dams to pups. These results demonstrate that DHA supplementation increased DHA and its metabolites in the mouse pup brain and alleviated the effects of MeHg on fetal brain development. Pregnant women's intake of fish containing high levels of DHA (or DHA supplementation) may help prevent MeHg-induced neurotoxicity in the fetus.
    Keywords:  Brain Lipids; Cytochrome P450; Omega-3 fatty acids; Pregnancy; Toxicology; dihydroxydocosapentaenoic acids (DHDPs); docosahexaenoic acid (DHA); methylmercury; neurotoxicity; soluble epoxide hydrolase (sEH)
    DOI:  https://doi.org/10.1016/j.jlr.2023.100458
  8. Neural Regen Res. 2024 Apr;19(4): 781-787
    Succinylation modification: a potential therapeutic target in stroke.
    Jie Lian, Wenwu Liu, Qin Hu, Xiaohua Zhang.
      Stroke is a leading cause of mortality and disability worldwide. Ischemic cell death triggered by the compromised supply of blood oxygen and glucose is one of the major pathophysiology of stroke-induced brain injury. Impaired mitochondrial energy metabolism is observed minutes after stroke and is closely associated with the progression of neuropathology. Recently, a new type of post-translational modification, known as lysine succinylation, has been recognized to play a significant role in mitochondrial energy metabolism after ischemia. However, the role of succinylation modification in cell metabolism after stroke and its regulation are not well understood. We aimed to review the effects of succinylation on energy metabolism, reactive oxygen species generation, and neuroinflammation, as well as Sirtuin 5 mediated desuccinylation after stroke. We also highlight the potential of targeting succinylation/desuccinylation as a promising strategy for the treatment of stroke. The succinylation level is dynamically regulated by the nonenzymatic or enzymatic transfer of a succinyl group to a protein on lysine residues and the removal of succinyl catalyzed by desuccinylases. Mounting evidence has suggested that succinylation can regulate the metabolic pathway through modulating the activity or stability of metabolic enzymes. Sirtuins, especially Sirtuin 5, are characterized for their desuccinylation activity and have been recognized as a critical regulator of metabolism through desuccinylating numerous metabolic enzymes. Imbalance between succinylation and desuccinylation has been implicated in the pathophysiology of stroke. Pharmacological agents that enhance the activity of Sirtuin 5 have been employed to promote desuccinylation and improve mitochondrial metabolism, and neuroprotective effects of these agents have been observed in experimental stroke studies. However, their therapeutic efficacy in stroke patients should be validated.
    Keywords:  mitochondria metabolism; neuroprotection; sirtuin 5; stroke; succinylation modification
    DOI:  https://doi.org/10.4103/1673-5374.382229
  9. Neural Regen Res. 2024 May;19(5): 951-952
    Autophagy in neuroinflammation after traumatic brain injury.
    Chinmoy Sarkar, Marta M Lipinski.
      
    DOI:  https://doi.org/10.4103/1673-5374.382247
  10. Neurochem Res. 2023 Oct 19.
    Modulation of Cellular Levels of Adenosine Phosphates and Creatine Phosphate in Cultured Primary Astrocytes.
    Gabriele Karger, Julius Berger, Ralf Dringen.
      Adenosine triphosphate (ATP) is the main energy currency of all cells, while creatine phosphate (CrP) is considered as a buffer of high energy-bond phosphate that facilitates rapid regeneration of ATP from adenosine diphosphate (ADP). Astrocyte-rich primary cultures contain ATP, ADP and adenosine monophosphate (AMP) in average specific contents of 36.0 ± 6.4 nmol/mg, 2.9 ± 2.1 nmol/mg and 1.7 ± 2.1 nmol/mg, respectively, which establish an adenylate energy charge of 0.92 ± 0.04. The average specific cellular CrP level was found to be 25.9 ± 10.8 nmol/mg and the CrP/ATP ratio was 0.74 ± 0.28. The specific cellular CrP content, but not the ATP content, declined with the age of the culture. Absence of fetal calf serum for 24 h caused a partial loss in the cellular contents of both CrP and ATP, while application of creatine for 24 h doubled the cellular CrP content and the CrP/ATP ratio, but did not affect ATP levels. In glucose-deprived astrocytes, the high cellular ATP and CrP contents were rapidly depleted within minutes after application of the glycolysis inhibitor 2-deoxyglucose and the respiratory chain inhibitor antimycin A. For those conditions, the decline in CrP levels always preceded that of ATP contents. In contrast, incubation of glucose-fed astrocytes for up to 30 min with antimycin A had little effect on the high cellular ATP content, while the CrP level was significantly lowered. These data demonstrate the importance of cellular CrP for maintaining a high cellular ATP content in astrocytes during episodes of impaired ATP regeneration.
    Keywords:  ATP; Astrocytes; Creatine; Metabolism; Mitochondria
    DOI:  https://doi.org/10.1007/s11064-023-04039-y
  11. Elife. 2023 Oct 16. pii: e91824. [Epub ahead of print]12
    Is creatine a CNS neurotransmitter?
    Bhagaban Mallik, C Andrew Frank.
      A range of experiments suggests that creatine, a molecule known for recycling ATP in muscle and brain tissue, may also function as a neurotransmitter in the central nervous system.
    Keywords:  AGAT; SLC6A8; astrocytes; creatine; inhibitory neurotransmission; mouse; neuroscience; synaptic vesicles
    DOI:  https://doi.org/10.7554/eLife.91824
  12. Endocr Metab Immune Disord Drug Targets. 2023 Oct 11.
    Evaluation of Mitochondrial Function on Pyruvate Dehydrogenase Complex Deficient Patient-derived Cell Lines.
    Hana Pavlú-Pereira, Cristina Florindo, Filipa Carvalho, Isabel Tavares de Almeida, Joao Vicente, Vanessa Morais, Isabel Rivera.
       INTRODUCTION: Pyruvate Dehydrogenase Complex (PDC) is a pivotal gatekeeper between cytosolic glycolysis and mitochondrial oxidative phosphorylation, playing important role in aerobic energy metabolism. Most PDC deficiency, cases being caused by mutations in PDHA1 encoding the α subunit of the rate-limiting E1 enzyme, which is characterized by abnormal phenotypes caused by energy deprivation at peripheral/central nervous systems and muscular tissues. This study aims to evaluate the potential therapeutic effect of arginine and thiamine in ameliorating mitochondrial function in patient-derived cultured cells.
    MATERIALS AND METHODS: PDC-deficient cell lines, carrying three different PDHA1 variants, were cultured in the absence and presence of arginine and/or thiamine at therapeutical levels, 4 mM and 100 μM, respectively. Mitochondrial bioenergetics profile was evaluated using the Seahorse extracellular flux analyzer.
    RESULTS: In physiological conditions, control cells presented standard values for all parameters evaluating the mitochondrial function, no differences being observed after supplementation of culture medium with therapeutic levels of arginine and/or thiamine. However, PDC-PDHA1 deficient cell lines consumed less oxygen than the control cells, but arginine and thiamine supplementation increased the basal respiration for values similar or higher than the control cell line. Moreover, arginine and thiamine treatment highlighted an inefficient oxidative phosphorylation carried out by PDC-deficient cell lines. Finally, this treatment showed an increased oxygen consumption by enzymes other than those in the respiratory chain, thus proving the dependence of these mutant cell lines on cytosolic sources for ATP production, namely glycolysis.
    CONCLUSIONS: This study showed that arginine and thiamine, at therapeutical levels, increase the basal oxygen consumption rate of PDC-deficient cell lines, as well as their ATP-linked respiration. This parameter measures the capacity of the cell to meet its energetic demands and, therefore, its increase reveals a higher electron flow through the respiratory chain, which is coupled to elevated oxidative phosphorylation, thus indicating an overall increased robustness in mitochondrial- related bioenergetics.
    Keywords:  arginine; energy metabolism; mitochondrial bioenergetics; pyruvate dehydrogenase complex; pyruvate dehydrogenase complex deficiency; thiamine
    DOI:  https://doi.org/10.2174/0118715303280072231004082458
  13. Neuroscience. 2023 Oct 18. pii: S0306-4522(23)00459-1. [Epub ahead of print]
    Abnormal microglial density and morphology in the brain of cyclooxygenase 2 knockin mice.
    Sarah Wheeler, Ravneet Rai-Bhogal, Dorota A Crawford.
      Prostaglandin E2 (PGE2) is a signaling molecule produced by cyclooxygenase-2 (COX-2) that is important in healthy brain development. Anomalies in the COX-2/PGE2 pathway due to genetic or environmental factors have been linked to Autism Spectrum Disorders (ASD). Our previous studies showed that COX-2 deficient (COX-2-KI) mice exhibit sex-dependent molecular changes in the brain and associated autism-related behaviors. Here, we aim to determine the effect of COX-2-KI on microglial density and morphology in the developing brain. Microglia normally transition between an amoeboid or ramified morphology depending on their surroundings and are important for the development of the healthy brain, assisting with synaptogenesis, synaptic pruning, and phagocytosis. We use COX-2-KI male and female mice to evaluate microglia density, morphology, and branch length and number in five brain regions (cerebellum, hippocampus, olfactory bulb, prefrontal cortex, and thalamus) at the gestational day 19 (G19) and postnatal day 25 (PN25). We discovered that COX2-KI females were affected at G19 with increased microglial density, altered percentage of amoeboid and ramified microglia, affected branch length, and decreased branching networks in a region-specific manner; these effects persisted to PN25 in select regions. Interestingly, while limited changes were found in G19 COX-2-KI males, at PN25 we found increased microglial density, higher percentages of ramified microglia, and increased branch counts, and length observed in nearly all brain regions tested. Overall, we show for the first time that the COX-2 deficiency in our ASD mouse model influences microglia morphology in a sex- and region- and stage-dependent manner.
    Keywords:  Autism Spectrum Disorder; Cell density; Microglia morphology; Neurodevelopmental disorders; Prostaglandin E2; Sex differences
    DOI:  https://doi.org/10.1016/j.neuroscience.2023.10.009
  14. Trends Cell Biol. 2023 Oct 17. pii: S0962-8924(23)00210-6. [Epub ahead of print]
    Control of mitochondrial dynamics by a fusogenic lipid.
    Zheng Yang, David C Chan.
      Mitochondrial fusion enables cooperation between the mitochondrial population and is critical for mitochondrial function. Phosphatidic acid (PA) on the mitochondrial surface has a key role in mitochondrial fusion. A recent study by Su et al. shows that the nucleoside diphosphate (NDP) kinase NME3 recognizes PA and mediates its effects on mitochondrial dynamics.
    Keywords:  membrane fusion; mitochondria; organelle; phospholipid
    DOI:  https://doi.org/10.1016/j.tcb.2023.10.006
  15. Nat Commun. 2023 Oct 16. 14(1): 6515
    Descending GABAergic pathway links brain sugar-sensing to peripheral nociceptive gating in Drosophila.
    Mami Nakamizo-Dojo, Kenichi Ishii, Jiro Yoshino, Masato Tsuji, Kazuo Emoto.
      Although painful stimuli elicit defensive responses including escape behavior for survival, starved animals often prioritize feeding over escape even in a noxious environment. This behavioral priority is typically mediated by suppression of noxious inputs through descending control in the brain, yet underlying molecular and cellular mechanisms are incompletely understood. Here we identify a cluster of GABAergic neurons in Drosophila larval brain, designated as SEZ-localized Descending GABAergic neurons (SDGs), that project descending axons onto the axon terminals of the peripheral nociceptive neurons and prevent presynaptic activity through GABAB receptors. Remarkably, glucose feeding to starved larvae causes sustained activation of SDGs through glucose-sensing neurons and subsequent insulin signaling in SDGs, which attenuates nociception and thereby suppresses escape behavior in response to multiple noxious stimuli. These findings illustrate a neural mechanism by which sugar sensing neurons in the brain engages descending GABAergic neurons in nociceptive gating to achieve hierarchical interaction between feeding and escape behavior.
    DOI:  https://doi.org/10.1038/s41467-023-42202-9
  16. Anal Bioanal Chem. 2023 Oct 20.
    Region-specific mouse brain ganglioside distribution revealed by an improved isobaric aminoxyTMT labeling strategy with automated data processing.
    Ryan A Smith, Qibin Zhang.
      Gangliosides are specialized glycosphingolipids most abundant in the central nervous system. Their complex amphiphilic structure is essential to the formation of membrane lipid rafts and for molecular recognition. Dysfunction of lipid rafts and ganglioside metabolism has been linked to cancer, metabolic disorders, and neurodegenerative disorders. Changes in ganglioside concentration and diversity during the progression of disease have made them potential biomarkers for early detection and shed light on disease mechanisms. Chemical derivatization facilitates whole ion analysis of gangliosides while improving ionization, providing rich fragmentation spectra, and enabling multiplexed analysis schemes such as stable isotope labeling. In this work, we report improvement to our previously reported isobaric labeling methodology for ganglioside analysis by increasing buffer concentration and removing solid-phase extraction desalting for a more complete and quantitative reaction. Identification and quantification of gangliosides are automated through MS-DIAL with an in-house ganglioside derivatives library. We have applied the updated methodology to relative quantification of gangliosides in six mouse brain regions (cerebellum, pons/medulla, midbrain, thalamus/hypothalamus, cortex, and basal ganglia) with 2 mg tissue per sample, and region-specific distributions of 88 ganglioside molecular species are described with ceramide isomers resolved. This method is promising for application to comparative analysis of gangliosides in biological samples.
    Keywords:  AminoxyTMT; Ceramide isomer; Ganglioside; Isobaric labeling; Mouse brain
    DOI:  https://doi.org/10.1007/s00216-023-04995-y
  17. Neurologia (Engl Ed). 2023 Oct 17. pii: S2173-5808(23)00057-3. [Epub ahead of print]
    Role of rafts in neurological disorders.
    Ulises Meza, Catalina Romero-Méndez, Sergio Sánchez-Armáss, Aldo A Rodríguez-Menchaca.
       INTRODUCTION: Rafts are protein-lipid structural nanodomains involved in efficient signal transduction and the modulation of physiological processes of the cell plasma membrane. Raft disruption in the nervous system has been associated with a wide range of disorders.
    DEVELOPMENT: We review the concept of rafts, the nervous system processes in which they are involved, and their role in such disorders as Parkinson's disease, Alzheimer disease, and Huntington disease.
    CONCLUSIONS: In view of the available evidence, preservation and/or reconstitution of rafts is a promising treatment strategy for a wide range of neurological disorders.
    Keywords:  Alzheimer; Alzheimer disease; Caveola; Colesterol; Huntington; Huntington disease; Membrana plasmática; Parkinson; Parkinson’s disease; caveolae; cholesterol; plasma membrane
    DOI:  https://doi.org/10.1016/j.nrleng.2023.10.003
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