bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2023‒06‒04
nineteen papers selected by
Regina F. Fernández
Johns Hopkins University
  1. Lactate shuttling as an allostatic means of thermoregulation in the brain.
  2. Glycogen phosphorylase isoenzyme GPbb versus GPmm regulation of ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and counter-regulatory hormone profiles during hypoglycemia: Role of L-lactate and octadecaneuropeptide.
  3. Exercise-induced hypothalamic neuroplasticity: Implications for energy and glucose metabolism.
  4. Juvenile CLN3 disease is a lysosomal cholesterol storage disorder: similarities with Niemann-Pick type C disease.
  5. Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D).
  6. Molecular and biophysical features of hippocampal "lipid rafts aging" are modified by dietary n-3 long-chain polyunsaturated fatty acids.
  7. Targeted Lipidomics Reveals a Novel Role for Glucosylceramides in Glucose Response.
  8. Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase.
  9. 13C Isotope Labeling and Mass Spectrometric Isotope Enrichment Analysis in Acute Brain Slices.
  10. Geometrical isomerization of arachidonic acid during lipid peroxidation interferes with ferroptosis.
  11. Free fatty acids support oligodendrocyte survival in a mouse model of amyotrophic lateral sclerosis.
  12. Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice.
  13. Integrated spatial transcriptome and metabolism study reveals metabolic heterogeneity in human injured brain.
  14. Brain glucose metabolism and gray matter volume in retired professional soccer players: a cross-sectional [18F]FDG-PET/MRI study.
  15. A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations.
  16. mTOR/α-ketoglutarate signaling: impact on brain cell homeostasis under ischemic conditions.
  17. Editorial: Neonatal and pediatric brain injury: novel therapeutics and perspective.
  18. The glycine receptor alpha 3 subunit mRNA expression shows sex-dependent differences in the adult mouse brain.
  19. Mitochondria as central hubs in synaptic modulation.
  1. Front Neurosci. 2023 ;17 1144639
    Lactate shuttling as an allostatic means of thermoregulation in the brain.
    Daniel A Kane, Alexander C Y Foo, Erin B Noftall, Karen Brebner, D Gerrard Marangoni.
      Lactate, the redox-balanced end product of glycolysis, travels within and between cells to fulfill an array of physiologic functions. While evidence for the centrality of this lactate shuttling in mammalian metabolism continues to mount, its application to physical bioenergetics remains underexplored. Lactate represents a metabolic "cul-de-sac," as it can only re-enter metabolism by first being converted back to pyruvate by lactate dehydrogenase (LDH). Given the differential distribution of lactate producing/consuming tissues during metabolic stresses (e.g., exercise), we hypothesize that lactate shuttling vis-à-vis the exchange of extracellular lactate between tissues serves a thermoregulatory function, i.e., an allostatic strategy to mitigate the consequences of elevated metabolic heat. To explore this idea, the rates of heat and respiratory oxygen consumption in saponin-permeabilized rat cortical brain samples fed lactate or pyruvate were measured. Heat and respiratory oxygen consumption rates, and calorespirometric ratios were lower during lactate vs. pyruvate-linked respiration. These results support the hypothesis of allostatic thermoregulation in the brain with lactate.
    Keywords:  bioenergetics; brain; calorimetry; lactate; mitochondria; pyruvate; thermal physiology
    DOI:  https://doi.org/10.3389/fnins.2023.1144639
  2. Mol Cell Neurosci. 2023 May 31. pii: S1044-7431(23)00057-X. [Epub ahead of print] 103863
    Glycogen phosphorylase isoenzyme GPbb versus GPmm regulation of ventromedial hypothalamic nucleus glucoregulatory neurotransmitter and counter-regulatory hormone profiles during hypoglycemia: Role of L-lactate and octadecaneuropeptide.
    Md Main Uddin, Md Haider Ali, A S M H Mahmood, Khaggeswar Bheemanapally, Jérôme Leprince, Karen P Briski.
      Glucose accesses the brain primarily via the astrocyte cell compartment, where it passes through the glycogen shunt before catabolism to the oxidizable fuel L-lactate. Glycogen phosphorylase (GP) isoenzymes GPbb and GPmm impose distinctive control of ventromedial hypothalamic nucleus (VMN) glucose-regulatory neurotransmission during hypoglycemia, but lactate and/or gliotransmitter involvement in those actions is unknown. Lactate or the octadecaneuropeptide receptor antagonist cyclo(1-8)[DLeu5] OP (LV-1075) did not affect gene product down-regulation caused by GPbb or GPmm siRNA, but suppressed non-targeted GP variant expression in a VMN region-specific manner. Hypoglycemic up-regulation of neuronal nitric oxide synthase was enhanced in rostral and caudal VMN by GPbb knockdown, yet attenuated by GPMM siRNA in the middle VMN; lactate or LV-1075 reversed these silencing effects. Hypoglycemic inhibition of glutamate decarboxylase65/67 was magnified by GPbb (middle and caudal VMN) or GPmm (middle VMN) knockdown, responses that were negated by lactate or LV-1075. GPbb or GPmm siRNA enlarged hypoglycemic VMN glycogen profiles in rostral and middle VMN. Lactate and LV-1075 elicited progressive rostral VMN glycogen augmentation in GPbb knockdown rats, but stepwise-diminution of rostral and middle VMN glycogen after GPmm silencing. GPbb, not GPmm, knockdown caused lactate or LV-1075 - reversible amplification of hypoglycemic hyperglucagonemia and hypercorticosteronemia. Results show that lactate and octadecaneuropeptide exert opposing control of GPbb protein in distinct VMN regions, while the latter stimulates GPmm. During hypoglycemia, GPbb and GPmm may respectively diminish (rostral, caudal VMN) or enhance (middle VMN) nitrergic transmission and each oppose GABAergic signaling (middle VMN) by lactate- and octadecaneuropeptide-dependent mechanisms.
    Keywords:  Corticosterone; Glycogen phosphorylase-brain type: Insulin-induced hypoglycemia; Glycogen phosphorylase-muscle type; Neuronal nitric oxide synthase; Octadecaneuropeptide
    DOI:  https://doi.org/10.1016/j.mcn.2023.103863
  3. Mol Metab. 2023 May 31. pii: S2212-8778(23)00079-0. [Epub ahead of print] 101745
    Exercise-induced hypothalamic neuroplasticity: Implications for energy and glucose metabolism.
    Eunsang Hwang, Bryan Portillo, Kyle Grose, Teppei Fujikawa, Kevin W Williams.
      BACKGROUND: Neuroplasticity refers to the brain's ability to undergo functional and structural changes in response to diverse challenges. Converging evidence supports the notion that exercise serves as a metabolic challenge, triggering the release of multiple factors both in the periphery and within the brain. These factors actively contribute to plasticity in the brain, and in turn, regulate energy and glucose metabolism.SCOPE OF REVIEW: The primary focus of this review is to explore the impact of exercise-induced plasticity in the brain on metabolic homeostasis, with an emphasis on the role of the hypothalamus in this process. Additionally, the review provides an overview of various factors induced by exercise that contribute to energy balance and glucose metabolism. Notably, these factors exert their effects, at least in part, through actions within the hypothalamus and more broadly in the central nervous system.
    MAJOR CONCLUSIONS: Exercise elicits both transient and sustained changes in metabolism, accompanied by changes in neural activity within specific brain regions. Importantly, the contribution of exercise-induced plasticity and the underlying mechanisms by which it influences the beneficial effects of exercise are not well understood. Recent work has begun to overcome this gap in knowledge by examining the complex interactions of exercise-induced factors which alter neural circuit properties to influence metabolism.
    DOI:  https://doi.org/10.1016/j.molmet.2023.101745
  4. EBioMedicine. 2023 May 26. pii: S2352-3964(23)00193-7. [Epub ahead of print]92 104628
    Juvenile CLN3 disease is a lysosomal cholesterol storage disorder: similarities with Niemann-Pick type C disease.
    Jacinda Chen, Rajesh Kumar Soni, Yimeng Xu, Sabrina Simoes, Feng-Xia Liang, Laura DeFreitas, Robert Hwang, Jorge Montesinos, Joseph H Lee, Estela Area-Gomez, Renu Nandakumar, Badri Vardarajan, Catherine Marquer.
      BACKGROUND: The most common form of neuronal ceroid lipofuscinosis (NCL) is juvenile CLN3 disease (JNCL), a currently incurable neurodegenerative disorder caused by mutations in the CLN3 gene. Based on our previous work and on the premise that CLN3 affects the trafficking of the cation-independent mannose-6 phosphate receptor and its ligand NPC2, we hypothesised that dysfunction of CLN3 leads to the aberrant accumulation of cholesterol in the late endosomes/lysosomes (LE/Lys) of JNCL patients' brains.METHODS: An immunopurification strategy was used to isolate intact LE/Lys from frozen autopsy brain samples. LE/Lys isolated from samples of JNCL patients were compared with age-matched unaffected controls and Niemann-Pick Type C (NPC) disease patients. Indeed, mutations in NPC1 or NPC2 result in the accumulation of cholesterol in LE/Lys of NPC disease samples, thus providing a positive control. The lipid and protein content of LE/Lys was then analysed using lipidomics and proteomics, respectively.
    FINDINGS: Lipid and protein profiles of LE/Lys isolated from JNCL patients were profoundly altered compared to controls. Importantly, cholesterol accumulated in LE/Lys of JNCL samples to a comparable extent than in NPC samples. Lipid profiles of LE/Lys were similar in JNCL and NPC patients, except for levels of bis(monoacylglycero)phosphate (BMP). Protein profiles detected in LE/Lys of JNCL and NPC patients appeared identical, except for levels of NPC1.
    INTERPRETATION: Our results support that JNCL is a lysosomal cholesterol storage disorder. Our findings also support that JNCL and NPC disease share pathogenic pathways leading to aberrant lysosomal accumulation of lipids and proteins, and thus suggest that the treatments available for NPC disease may be beneficial to JNCL patients. This work opens new avenues for further mechanistic studies in model systems of JNCL and possible therapeutic interventions for this disorder.
    FUNDING: San Francisco Foundation.
    Keywords:  Cholesterol; Human brain tissue; Juvenile CLN3 disease; Lysosomes; Niemann–Pick type C disease; Proteomics
    DOI:  https://doi.org/10.1016/j.ebiom.2023.104628
  5. Sci Rep. 2023 Jun 02. 13(1): 8951
    Combination of triheptanoin with the ketogenic diet in Glucose transporter type 1 deficiency (G1D).
    Adrian Avila, Ignacio Málaga, Deepa Sirsi, Saima Kayani, Sharon Primeaux, Gauri A Kathote, Vikram Jakkamsetti, Raja Reddy Kallem, William C Putnam, Jason Y Park, Shlomo Shinnar, Juan M Pascual.
      Fuel influx and metabolism replenish carbon lost during normal neural activity. Ketogenic diets studied in epilepsy, dementia and other disorders do not sustain such replenishment because their ketone body derivatives contain four carbon atoms and are thus devoid of this anaplerotic or net carbon donor capacity. Yet, in these diseases carbon depletion is often inferred from cerebral fluorodeoxyglucose-positron emission tomography. Further, ketogenic diets may prove incompletely therapeutic. These deficiencies provide the motivation for complementation with anaplerotic fuel. However, there are few anaplerotic precursors consumable in clinically sufficient quantities besides those that supply glucose. Five-carbon ketones, stemming from metabolism of the food supplement triheptanoin, are anaplerotic. Triheptanoin can favorably affect Glucose transporter type 1 deficiency (G1D), a carbon-deficiency encephalopathy. However, the triheptanoin constituent heptanoate can compete with ketogenic diet-derived octanoate for metabolism in animals. It can also fuel neoglucogenesis, thus preempting ketosis. These uncertainties can be further accentuated by individual variability in ketogenesis. Therefore, human investigation is essential. Consequently, we examined the compatibility of triheptanoin at maximum tolerable dose with the ketogenic diet in 10 G1D individuals using clinical and electroencephalographic analyses, glycemia, and four- and five-carbon ketosis. 4 of 8 of subjects with pre-triheptanoin beta-hydroxybutyrate levels greater than 2 mM demonstrated a significant reduction in ketosis after triheptanoin. Changes in this and the other measures allowed us to deem the two treatments compatible in the same number of individuals, or 50% of persons in significant beta-hydroxybutyrate ketosis. These results inform the development of individualized anaplerotic modifications to the ketogenic diet.ClinicalTrials.gov registration NCT03301532, first registration: 04/10/2017.
    DOI:  https://doi.org/10.1038/s41598-023-36001-x
  6. Aging Cell. 2023 May 30. e13867
    Molecular and biophysical features of hippocampal "lipid rafts aging" are modified by dietary n-3 long-chain polyunsaturated fatty acids.
    Mario Díaz, Daniel Pereda de Pablo, Catalina Valdés-Baizabal, Guido Santos, Raquel Marin.
      "Lipid raft aging" in nerve cells represents an early event in the development of aging-related neurodegenerative diseases, such as Alzheimer's disease. Lipid rafts are key elements in synaptic plasticity, and their modification with aging alters interactions and distribution of signaling molecules, such as glutamate receptors and ion channels involved in memory formation, eventually leading to cognitive decline. In the present study, we have analyzed, in vivo, the effects of dietary supplementation of n-3 LCPUFA on the lipid structure, membrane microviscosity, domain organization, and partitioning of ionotropic and metabotropic glutamate receptors in hippocampal lipid raffs in female mice. The results revealed several lipid signatures of "lipid rafts aging" in old mice fed control diets, consisting in depletion of n-3 LCPUFA, membrane unsaturation, along with increased levels of saturates, plasmalogens, and sterol esters, as well as altered lipid relevant indexes. These changes were paralleled by increased microviscosity and changes in the raft/non-raft (R/NR) distribution of AMPA-R and mGluR5. Administration of the n-3 LCPUFA diet caused the partial reversion of fatty acid alterations found in aged mice and returned membrane microviscosity to values found in young animals. Paralleling these findings, lipid rafts accumulated mGluR5, NMDA-R, and ASIC2, and increased their R/NR proportions, which collectively indicate changes in synaptic plasticity. Unexpectedly, this diet also modified the lipidome and dimension of lipid rafts, as well as the domain redistribution of glutamate receptors and acid-sensing ion channels involved in hippocampal synaptic plasticity, likely modulating functionality of lipid rafts in memory formation and reluctance to age-associated cognitive decline.
    Keywords:  AMPA-R; Aging; DHA; NMDA-R; acid-sensing ion channels; arachidonic acid; cholesterol; dietary LCPUFA; fluidity; ganglioside GM1; lipid rafts; mGlu-R; membrane microdomains; microviscosity; sphingolipids
    DOI:  https://doi.org/10.1111/acel.13867
  7. J Lipid Res. 2023 May 26. pii: S0022-2275(23)00067-6. [Epub ahead of print] 100394
    Targeted Lipidomics Reveals a Novel Role for Glucosylceramides in Glucose Response.
    Mark A Xatse, Andre F C Vieira, Chloe Byrne, Carissa Perez Olsen.
      The addition of excess glucose to the diet drives a coordinated response of lipid metabolism pathways to tune the membrane composition to the altered diet. Here, we have employed targeted lipidomic approaches to quantify the specific changes in the phospholipid and sphingolipid populations that occur in elevated glucose conditions. The lipids within wildtype Caenorhabditis elegans are strikingly stable with no significant changes identified in our global mass spectrometry-based analysis. Previous work has identified ELO-5, an elongase that is critical for the synthesis of monomethyl-branched chain fatty acids (mmBCFAs), as essential for surviving elevated glucose conditions. Therefore, we performed targeted lipidomics on elo-5 RNAi-fed animals and identified several significant changes in these animals in lipid species that contain mmBCFAs as well as in species that do not contain mmBCFAs. Of particular note, we identified a specific glucosylceramide (GlcCer 17:1;O2/22:0;O) that is also significantly upregulated with glucose in wildtype animals. Furthermore, compromising the production of the glucosylceramide pool with elo-3 or cgt-3 RNAi leads to premature death in glucose-fed animals. Taken together, our lipid analysis has expanded the mechanistic understanding of metabolic rewiring with glucose feeding and has identified a new role for the GlcCer 17:1;O2/22:0;O.
    Keywords:  Caenorhabditis elegans.; RNAi; elevated glucose conditions; elongase; lipid metabolism pathways; mass spectrometry; membrane composition; monomethyl-branched chain fatty acids; phospholipids; sphingolipids
    DOI:  https://doi.org/10.1016/j.jlr.2023.100394
  8. Biochim Biophys Acta Mol Basis Dis. 2023 May 29. pii: S0925-4439(23)00132-1. [Epub ahead of print] 166766
    Functional and structural impact of 10 ACADM missense mutations on human medium chain acyl-Coa dehydrogenase.
    Catarina A Madeira, Carolina Anselmo, João M Costa, Cátia A Bonito, Ricardo J Ferreira, Daniel J V A Santos, Ronald Wanders, João B Vicente, Fátima V Ventura, Paula Leandro.
      Medium chain acyl-CoA dehydrogenase (MCAD) deficiency (MCADD) is associated with ACADM gene mutations, leading to an impaired function and/or structure of MCAD. Importantly, after import into the mitochondria, MCAD must incorporate a molecule of flavin adenine dinucleotide (FAD) per subunit and assemble into tetramers. However, the effect of MCAD amino acid substitutions on FAD incorporation has not been investigated. Herein, the commonest MCAD variant (p.K304E) and 11 additional rare variants (p.Y48C, p.R55G, p.A88P, p.Y133C, p.A140T, p.D143V, p.G224R, p.L238F, p.V264I, p.Y372N, and p.G377V) were functionally and structurally characterized. Half of the studied variants presented a FAD content <65 % compared to the wild-type. Most of them were recovered as tetramers, except the p.Y372N (mainly as dimers). No correlation was found between the levels of tetramers and FAD content. However, a correlation between FAD content and the cofactor's affinity, proteolytic stability, thermostability, and thermal inactivation was established. We showed that the studied amino acid changes in MCAD may alter the substrate chain-length dependence and the interaction with electron-transferring-flavoprotein (ETF) necessary for a proper functioning electron transfer thus adding additional layers of complexity to the pathological effect of ACADM missense mutations. Although the majority of the variant MCADs presented an impaired capacity to retain FAD during their synthesis, some of them were structurally rescued by cofactor supplementation, suggesting that in the mitochondrial environment the levels and activity of those variants may be dependent of FAD's availability thus contributing for the heterogeneity of the MCADD phenotype found in patients presenting the same genotype.
    Keywords:  Disease-causing mutations; Electron transferring flavoprotein; Flavin adenine dinucleotide; Inborn metabolic disorders; Medium chain acyl-CoA dehydrogenase deficiency; Protein misfolding
    DOI:  https://doi.org/10.1016/j.bbadis.2023.166766
  9. Methods Mol Biol. 2023 ;2675 181-194
    13C Isotope Labeling and Mass Spectrometric Isotope Enrichment Analysis in Acute Brain Slices.
    Elisa Motori, Patrick Giavalisco.
      Feeding of stable 13C-labeled compounds coupled to mass spectrometric analysis has enabled the characterization of dynamic metabolite partitioning in various experimental conditions. This information is particularly relevant for the study and functional understanding of brain metabolic heterogeneity. We here describe a protocol for the analysis of metabolic enrichment analysis upon feeding of murine acute cerebellar slices with 13C-labeled substrates.
    Keywords:  13C labeling; Brain slices; Cellular metabolism; Cerebellum; Isotope enrichment; Liquid chromatography; Mass spectrometry
    DOI:  https://doi.org/10.1007/978-1-0716-3247-5_14
  10. Free Radic Biol Med. 2023 May 29. pii: S0891-5849(23)00461-6. [Epub ahead of print]
    Geometrical isomerization of arachidonic acid during lipid peroxidation interferes with ferroptosis.
    Yusuke Hirata, Carla Ferreri, Yuto Yamada, Aya Inoue, Anna Sansone, Fabrizio Vetica, Wakana Suzuki, Saya Takano, Takuya Noguchi, Atsushi Matsuzawa, Chryssostomos Chatgilialoglu.
      Geometrical mono-trans isomers of arachidonic acid (mtAA) are endogenous products of free radical-induced cis-trans double bond isomerization occurring to natural fatty acids during cell metabolism, including lipid peroxidation (LPO). Very little is known about the functional roles of mtAA and in general on the effects of mono-trans isomers of polyunsaturated fatty acids (mtPUFA) in various types of programmed cell death, including ferroptosis. Using HT1080 and MEF cell cultures, supplemented with 20 μM PUFA (i.e., AA, EPA or DHA) and their mtPUFA congeners, ferroptosis occurred in the presence of RSL3 (a direct inhibitor of glutathione peroxidase 4) only with the PUFA in their natural cis configuration, whereas mtPUFA showed an anti-ferroptotic effect. By performing the fatty acid-based membrane lipidome analyses, substantial differences emerged in the membrane fatty acid remodeling of the two different cell fates. In particular, during ferroptosis mtPUFA formation and their incorporation, together with the enrichment of SFA, occurred. This opens new perspectives in the role of the membrane composition for a ferroptotic outcome. While pre-treatment with AA promoted cell death for treatment with H2O2 and RSL3, mtAA did not. Cell death by AA supplementation was suppressed also in the presence of either ferroptosis inhibitors, such as the lipophilic antioxidant ferrostatin-1, or NADPH oxidase (NOX) inhibitors, including diphenyleneiodonium chloride and apocynin. Our results confirm a more complex scenario for ferroptosis than actually believed. While LPO processes are active, the importance of environmental lipid levels, balance among SFA, MUFA and PUFA in lipid pools and formation of mtPUFA influence the membrane phospholipid turnover, with crucial effects in the occurrence of cell death by ferroptosis.
    Keywords:  Ferroptosis; Free radicals; Lipid peroxidation; NADPH oxidase; Polyunsaturated fatty acids; Trans-Fatty acids; cis-Trans isomerization
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2023.05.026
  11. Front Cell Neurosci. 2023 ;17 1081190
    Free fatty acids support oligodendrocyte survival in a mouse model of amyotrophic lateral sclerosis.
    Takashi Maruyama, Shogo Tanabe, Akiko Uyeda, Tatsunori Suzuki, Rieko Muramatsu.
      Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the white matter degeneration. Although changes in blood lipids are involved in the pathogenesis of neurological diseases, the pathological role of blood lipids in ALS remains unclear.Methods and results: We performed lipidome analysis on the plasma of ALS model mice, mutant superoxide dismutase 1 (SOD1G93A) mice, and found that the concentration of free fatty acids (FFAs), including oleic acid (OA) and linoleic acid (LA), decreased prior to disease onset. An in vitro study revealed that OA and LA directly inhibited glutamate-induced oligodendrocytes cell death via free fatty acid receptor 1 (FFAR1). A cocktail containing OA/LA suppressed oligodendrocyte cell death in the spinal cord of SOD1G93A mice.
    Discussion: These results suggested that the reduction of FFAs in the plasma is a pathogenic biomarker for ALS in the early stages, and supplying a deficiency in FFAs is a potential therapeutic approach for ALS by preventing oligodendrocyte cell death.
    Keywords:  SOD1; amyotrophic lateral sclerosis (ALS); free fatty acids; lipidome; oligodendrocyte
    DOI:  https://doi.org/10.3389/fncel.2023.1081190
  12. Front Mol Neurosci. 2023 ;16 1175851
    Progressive mitochondrial dysfunction in cerebellar synaptosomes of cystatin B-deficient mice.
    Katarin Gorski, Christopher B Jackson, Tuula A Nyman, Veronika Rezov, Brendan J Battersby, Anna-Elina Lehesjoki.
      The involvement of mitochondrial dysfunction in cystatin B (CSTB) deficiency has been suggested, but its role in the onset of neurodegeneration, myoclonus, and ataxia in the CSTB-deficient mouse model (Cstb-/-) is yet unknown. CSTB is an inhibitor of lysosomal and nuclear cysteine cathepsins. In humans, partial loss-of-function mutations cause the progressive myoclonus epilepsy neurodegenerative disorder, EPM1. Here we applied proteome analysis and respirometry on cerebellar synaptosomes from early symptomatic (Cstb-/-) mice to identify the molecular mechanisms involved in the onset of CSTB-deficiency associated neural pathogenesis. Proteome analysis showed that CSTB deficiency is associated with differential expression of mitochondrial and synaptic proteins, and respirometry revealed a progressive impairment in mitochondrial function coinciding with the onset of myoclonus and neurodegeneration in (Cstb-/-) mice. This mitochondrial dysfunction was not associated with alterations in mitochondrial DNA copy number or membrane ultrastructure. Collectively, our results show that CSTB deficiency generates a defect in synaptic mitochondrial bioenergetics that coincides with the onset and progression of the clinical phenotypes, and thus is likely a contributor to the pathogenesis of EPM1.
    Keywords:  OXPHOS; mitochondria; myoclonus; neurodegeneration; proteomics; respiration; synaptosome
    DOI:  https://doi.org/10.3389/fnmol.2023.1175851
  13. Cell Rep Med. 2023 May 20. pii: S2666-3791(23)00171-4. [Epub ahead of print] 101057
    Integrated spatial transcriptome and metabolism study reveals metabolic heterogeneity in human injured brain.
    Ping Zheng, Ning Zhang, Dabin Ren, Cong Yu, Bin Zhao, Yisong Zhang.
      Single-cell transcriptomics can provide quantitative molecular signatures for large, unbiased samples of the diverse cell types in the brain. With the advances of multi-omics datasets, a major challenge is to validate and integrate results into a biological understanding of spatial organization and functional orientation. Here, we generate spatial transcriptomes and metabolites from six patients with brain trauma with surgical samples. The resulting spatial marker gene, which is highly replicable across analysis methods, sequencing technologies, and modalities, is a comprehensive molecular marker of the diverse metabolic changes in human injured brains. The atlas includes an area of lipid peroxidation that resembles injured neurons in the brain. We further discover imbalanced myo-inositol and myo-inositol phosphate and related spatial markers. Our results highlight the complex transcriptomic regulation and metabolic alterations in the injured brain and will directly enable the design of reagents to target specific genes in the human brain for functional analysis.
    Keywords:  metabolic heterogeneity; spatial metabolism; spatial transcriptome; traumatic brain injury
    DOI:  https://doi.org/10.1016/j.xcrm.2023.101057
  14. Arq Neuropsiquiatr. 2023 May;81(5): 433-443
    Brain glucose metabolism and gray matter volume in retired professional soccer players: a cross-sectional [18F]FDG-PET/MRI study.
    Mateus Rozalem Aranha, Artur Martins Coutinho, Camila de Godoi Carneiro, Bruno Fraccini Pastorello, Adalberto Studart-Neto, Carla Cristina Guariglia, Miriam Harumi Tsunemi, Everton Luis Santos Moreira, Jéssica Natuline Ianof, Renato Anghinah, Ricardo Nitrini, Giovanni Guido Cerri, Juan Fortea, Carlos Alberto Buchpiguel, Claudia Costa Leite.
      BACKGROUND:  Professional soccer athletes are exposed to repetitive head impacts and are at risk of developing chronic traumatic encephalopathy.OBJECTIVE:  To evaluate regional brain glucose metabolism (rBGM) and gray matter (GM) volume in retired soccer players (RSPs).
    METHODS:  Male RSPs and age and sex-matched controls prospectively enrolled between 2017 and 2019 underwent neurological and neuropsychological evaluations, brain MRI and [18F]FDG-PET in a 3.0-Tesla PET/MRI scanner. Visual analysis was performed by a blinded neuroradiologist and a blinded nuclear physician. Regional brain glucose metabolism and GM volume were assessed using SPM8 software. Groups were compared using appropriate statistical tests available at SPM8 and R.
    RESULTS:  Nineteen RSPs (median [IQR]: 62 [50-64.5] years old) and 20 controls (60 [48-73] years old) were included. Retired soccer players performed worse on mini-mental state examination, digit span, clock drawing, phonemic and semantic verbal fluency tests, and had reduced rBGM in the left temporal pole (pFDR = 0.008) and the anterior left middle temporal gyrus (pFDR = 0.043). Semantic verbal fluency correlated with rBGM in the right hippocampus, left temporal pole, and posterior left middle temporal gyrus (p ≤ 0.042). Gray matter volume reduction was observed in similar anatomic regions but was less extensive and did not survive correction for multiple comparisons (pFDR ≥ 0.085). Individual [18F]FDG-PET visual analysis revealed seven RSPs with overt hypometabolism in the medial and lateral temporal lobes, frontal lobes, and temporoparietal regions. Retired soccer players had a higher prevalence of septum pellucidum abnormalities on MRI.
    CONCLUSION:  Retired soccer players had reduced rBGM and GM volume in the temporal lobes and septum pellucidum abnormalities, findings possibly related to repetitive head impacts.
    DOI:  https://doi.org/10.1055/s-0043-1768666
  15. Front Aging Neurosci. 2023 ;15 1151848
    A Y374X TDP43 truncation leads to an altered metabolic profile in amyotrophic lateral sclerosis fibroblasts driven by pyruvate and TCA cycle intermediate alterations.
    Scott P Allen, Afnan Al Sultan, Elaine Kabucho Kibirige, Erin Tonkiss, Keaton J Hamer, Lydia M Castelli, Ya-Hui Lin, Sarah Roscoe, Nikolaos Stefanidis, Richard J Mead, J Robin Highley, Johnathan Cooper-Knock, Guillaume M Hautbergue, Paul R Heath, Janine Kirby, Pamela J Shaw.
      A p.Y374X truncation in TARDBP was recently shown to reduce expression of TDP43 in fibroblasts isolated from ALS cases. In this follow up study focused on assessing the downstream phenotypic consequences of loss of TDP43 in the context of the truncation, we have shown a striking effect on the fibroblast metabolic profile. Phenotypic metabolic screening uncovered a distinct metabolic profile in TDP43-Y374X fibroblasts compared to controls, which was driven by alterations in key metabolic checkpoint intermediates including pyruvate, alpha-ketoglutarate and succinate. These metabolic alterations were confirmed using transcriptomics and bioenergetic flux analysis. These data suggest that TDP43 truncation directly compromises glycolytic and mitochondrial function, identifying potential therapeutic targets for mitigating the effects of TDP43-Y374X truncation.
    Keywords:  ALS; TCA; fibroblasts; metabolism; metabolomics; pyruvate; transcriptomics
    DOI:  https://doi.org/10.3389/fnagi.2023.1151848
  16. Front Cell Neurosci. 2023 ;17 1132114
    mTOR/α-ketoglutarate signaling: impact on brain cell homeostasis under ischemic conditions.
    Iryna Lushnikova, Olha Kostiuchenko, Magdalena Kowalczyk, Galyna Skibo.
      The multifunctional molecules mechanistic target of rapamycin (mTOR) and α-ketoglutarate (αKG) are crucial players in the regulatory mechanisms that maintain cell homeostasis in an ever-changing environment. Cerebral ischemia is associated primarily with oxygen-glucose deficiency (OGD) due to circulatory disorders. Upon exceeding a threshold of resistance to OGD, essential pathways of cellular metabolism can be disrupted, leading to damage of brain cells up to the loss of function and death. This mini-review focuses on the role of mTOR and αKG signaling in the metabolic homeostasis of brain cells under OGD conditions. Integral mechanisms concerning the relative cell resistance to OGD and the molecular basis of αKG-mediated neuroprotection are discussed. The study of molecular events associated with cerebral ischemia and endogenous neuroprotection is relevant for improving the effectiveness of therapeutic strategies.
    Keywords:  autophagy; brain ischemia; homeostasis; mTOR; neuroprotection; α-ketoglutarate (αKG)
    DOI:  https://doi.org/10.3389/fncel.2023.1132114
  17. Front Pediatr. 2023 ;11 1210749
    Editorial: Neonatal and pediatric brain injury: novel therapeutics and perspective.
    Takeo Mukai, Rafael Galindo, Jacques-Olivier Coq.
      
    Keywords:  hypoxic-ischemic encephalopathy; neonatal brain injury; pediatric brain injury; stroke; traumatic brain injury
    DOI:  https://doi.org/10.3389/fped.2023.1210749
  18. BMC Neurosci. 2023 Jun 01. 24(1): 32
    The glycine receptor alpha 3 subunit mRNA expression shows sex-dependent differences in the adult mouse brain.
    Mikaela M Ceder, Hannah M Weman, Ebba Johansson, Katharina Henriksson, Kajsa A Magnusson, Erika Roman, Malin C Lagerström.
      BACKGROUND: The glycinergic system plays an important inhibitory role in the mouse central nervous system, where glycine controls the excitability of spinal itch- and pain-mediating neurons. Impairments of the glycine receptors can cause motor and sensory deficits. Glycine exerts inhibition through interaction with ligand-gated ion channels composed of alpha and beta subunits. We have investigated the mRNA expression of the glycine receptor alpha 3 (Glra3) subunit in the nervous system as well as in several peripheral organs of female and male mice.RESULTS: Single-cell RNA sequencing (scRNA-seq) data analysis on the Zeisel et al. (2018) dataset indicated widespread but low expression of Glra3 in vesicular glutamate transporter 2 (Vglut2, Slc17a6) positive and vesicular inhibitory amino acid transporter (Viaat, Slc32a1)positive neurons of the mouse central nervous system. Highest occurrence of Glra3 expression was identified in the cortex, amygdala, and striatal regions, as well as in the hypothalamus, brainstem and spinal cord. Bulk quantitative real-time-PCR (qRT-PCR) analysis demonstrated Glra3 expression in cortex, amygdala, striatum, hypothalamus, thalamus, pituitary gland, hippocampus, cerebellum, brainstem, and spinal cord. Additionally, male mice expressed higher levels of Glra3 in all investigated brain areas compared with female mice. Lastly, RNAscope spatially validated Glra3 expression in the areas indicated by the single-cell and bulk analyses. Moreover, RNAscope analysis confirmed co-localization of Glra3 with Slc17a6 or Slc32a1 in the central nervous system areas suggested from the single-cell data.
    CONCLUSIONS: Glra3 expression is low but widespread in the mouse central nervous system. Clear sex-dependent differences have been identified, indicating higher levels of Glra3 in several telencephalic and diencephalic areas, as well as in cerebellum and brainstem, in male mice compared with female mice.
    Keywords:  Brain; Glra3; Glycine; Mice; Sex-dependent differences; Spinal cord
    DOI:  https://doi.org/10.1186/s12868-023-00800-9
  19. Cell Mol Life Sci. 2023 Jun 02. 80(6): 173
    Mitochondria as central hubs in synaptic modulation.
    Filipe V Duarte, Daniele Ciampi, Carlos B Duarte.
      Mitochondria are present in the pre- and post-synaptic regions, providing the energy required for the activity of these very specialized neuronal compartments. Biogenesis of synaptic mitochondria takes place in the cell body, and these organelles are then transported to the synapse by motor proteins that carry their cargo along microtubule tracks. The transport of mitochondria along neurites is a highly regulated process, being modulated by the pattern of neuronal activity and by extracellular cues that interact with surface receptors. These signals act by controlling the distribution of mitochondria and by regulating their activity. Therefore, mitochondria activity at the synapse allows the integration of different signals and the organelles are important players in the response to synaptic stimulation. Herein we review the available evidence regarding the regulation of mitochondrial dynamics by neuronal activity and by neuromodulators, and how these changes in the activity of mitochondria affect synaptic communication.
    Keywords:  Cannabinoid receptors; Intracellular signalling; Intracellular trafficking; Mitochondria; Neurotrophins; Synaptic regulation
    DOI:  https://doi.org/10.1007/s00018-023-04814-8
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