bims-medebr Biomed News
on Metabolism of the developing brain
Issue of 2026–09–20
eighteen papers selected by
Regina F. Fernández, Johns Hopkins University
  1. APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics.
  2. Cholesterol Quantification in Brain and Spinal Cord During Development, Demyelination, and Remyelination.
  3. The role of impaired mitochondrial function in neurological manifestations of mitochondrial diseases.
  4. Metabolism and oxygen tension in Alzheimer's disease mouse model using two-photon FLIM-PLIM microscopy.
  5. Significance of NAD anabolism profiles in neurological diseases.
  6. Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway.
  7. Age-dependent changes in lipid droplet distribution and vascularization in naked mole rat vs. mouse hippocampus.
  8. PDE5 inhibition restores mitochondrial function and improves neurobehavioral outcomes after repeated mild blast TBI.
  9. Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.
  10. Lactate Metabolism and Signaling in Amyotrophic Lateral Sclerosis.
  11. L-serine-enriched diet restores impaired adult neurogenesis in the hippocampus of 3xTg-AD mice.
  12. Defective neuronal differentiation in Lowe syndrome is associated with mitochondrial dysfunction and impaired cilia-related Sonic Hedgehog signaling.
  13. PEX11β controls early neural progenitor fate through regulation of peroxisomal fission and lipid metabolism.
  14. The Batten disease protein CLN8 is a stereospecific acyltransferase in bis(monoacylglycero)phosphate biosynthesis.
  15. The longevity gene APOE2 enhances pericyte function and reduces lipid droplets.
  16. PET-MRI effects of N-acetylcysteine in patients with multiple sclerosis.
  17. Endothelial SLC38A2 controls brain D-serine homeostasis and synapse development.
  18. Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.
  1. Nat Commun. 2026 08 19. pii: 9900. [Epub ahead of print]17(1):
    APOE genotypes differentially remodel the astrocytic lipid droplet proteome to shape lipid droplet dynamics.
    Carla Cuní-López, Jessica T Root, Ying Hao, Niek Blomberg, Sascha J Koppes-den Hertog, Dylan Sacks, Amber E Trujillo, Rodolfo Ghirlando, Isabelle Kowal, Jacob Epstein, Linda G Yang, Mark R Cookson, Elise Marsan, Rik van der Kant, Martin Giera, Yue Andy Qi, Priyanka S Narayan.
      Lipid droplets are dynamic cellular organelles that store neutral lipids and coordinate metabolic and stress-response pathways. In the brain, lipid droplets in glial cells, including astrocytes, have been implicated in Alzheimer's disease, but how genetic risk factors influence their composition and turnover remains poorly understood. APOE is the strongest genetic modulator of late-onset Alzheimer's disease and exists in common variants that confer decreased, neutral, or increased risk. Here we show that APOE genotype shapes the lipid droplet proteome, lipidome, and degradation dynamics in human induced pluripotent stem cell-derived astrocytes. By comparing oleic acid-treated astrocytes carrying APOE2, APOE3, or APOE4, we find that each variant is associated with distinct lipid droplet proteins and lipids. These molecular differences correspond to genotype-dependent changes in lipophagy, an autophagy-mediated pathway for lipid droplet clearance. Lipid droplets in APOE2 astrocytes undergo efficient autophagic turnover, whereas those in APOE4 astrocytes resist degradation. These findings identify impaired lipid droplet clearance as a potential mechanism linking APOE4 to Alzheimer's disease risk.
    DOI:  https://doi.org/10.1038/s41467-026-76565-6
  2. Molecules. 2026 Aug 28. pii: 3033. [Epub ahead of print]31(17):
    Cholesterol Quantification in Brain and Spinal Cord During Development, Demyelination, and Remyelination.
    Disni Dedunupitiya, Eden P Go, Travis Witte, Ashlynn Elliott, Nishama De Silva Mohotti, Jenna M Williams, Hiroko Kobayashi, Rashmi Binjawadagi, Heather Desaire, Meredith D Hartley.
      Cholesterol in the central nervous system (CNS) is largely unesterified (>99%) and is predominantly present in the myelin sheath (~70% of total CNS cholesterol). However, cholesterol ester accumulation has been observed during neurological disease. In this cross-sectional study, we measured free cholesterol and cholesterol ester levels in the brains and the spinal cords of Plp1-iCKO-Myrf mouse model during postnatal myelination, demyelination, and remyelination using gas chromatography-mass spectrometry with single ion monitoring (GC-MS-SIM) and liquid chromatography-mass spectrometry (LC-MS). Cholesterol levels in healthy mouse brains increased steadily up to 38 weeks of age. In contrast, cholesterol in the healthy spinal cord increased until P42, and then remained steady out to 38 weeks of age. During demyelination, both brain and spinal cord cholesterol levels were significantly reduced compared to healthy mice and did not return to normal cholesterol levels even during remyelination. Semi-quantitative quantification of cholesterol esters during peak demyelination revealed that cholesterol esters comprise 19% of the measured cholesterol pool in the brain and 66% in the spinal cord. Robust methods for internal standard-based quantification of CNS cholesterol and cholesterol esters were developed, which are critical for revealing mechanisms of cholesterol regulation during disease.
    Keywords:  cholesterol; cholesterol esters; demyelination; gas chromatography mass spectrometry (GC-MS); liquid chromatography–mass spectrometry (LC-MS); multiple sclerosis; myelin; myelin repair; remyelination
    DOI:  https://doi.org/10.3390/molecules31173033
  3. Mamm Genome. 2026 Sep 18. pii: 108. [Epub ahead of print]37(1):
    The role of impaired mitochondrial function in neurological manifestations of mitochondrial diseases.
    Danielle Brister, Mariana Zarate-Mendez, Denisa Hathazi, Rita Horvath.
      Mitochondria are essential organelles responsible for cellular energy production and the regulation of key metabolic and signalling pathways. Their function depends on the coordinated expression of both mitochondrial and nuclear genomes, and mitochondrial dysfunction leads to a diverse group of mitochondrial diseases. The nervous system is particularly vulnerable to mitochondrial dysfunction due to the high energetic demands and complex morphology of neurons. Neurons rely heavily on mitochondrial ATP production to support processes such as synaptic transmission, axonal transport, and calcium homeostasis, which are tightly regulated by mitochondrial dynamics, intracellular trafficking, and quality control mechanisms. In mitochondrial diseases, impairment of these processes contributes to a range of neurological manifestations, including epilepsy, stroke-like episodes, Leigh syndrome, ataxia, and peripheral neuropathy. Despite the ubiquitous presence of mitochondria, neuronal vulnerability varies between distinct neuronal populations, reflecting differences in neuronal morphology and metabolic demands. This review summarises key mechanisms underlying neuronal susceptibility in mitochondrial disease and highlights how defects in mitochondrial bioenergetics, dynamics, and transport contribute to characteristic neurological phenotypes. Understanding these mechanisms may provide insights into tissue-specific vulnerability and identify potential therapeutic targets to treat mitochondrial diseases and other neurodegenerative disorders associated with mitochondrial mechanisms.
    DOI:  https://doi.org/10.1007/s00335-026-10278-5
  4. Neurophotonics. 2026 Jul;13(3): 035008
    Metabolism and oxygen tension in Alzheimer's disease mouse model using two-photon FLIM-PLIM microscopy.
    Vijay Kumar Sagar, Horst Wallrabe, Shagufta Rehman Alam, Evelyn Pardo, Wolfgang Becker, Andrés Norambuena, Ammasi Periasamy.
       Significance: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory deficits, processes critically linked to mitochondrial dysfunction in the nervous system. Equally, adequate brain tissue oxygenation is essential for cerebral metabolism, and its impairment further compromises neuronal energy homeostasis. Together, mitochondrial dysfunction and disrupted cerebral oxygenation represent key interconnected pathological mechanisms underlying AD progression, highlighting the significance of targeting these pathways in understanding and managing the disease.
    Aim: Cerebral energy metabolism in the cortex of wild-type (WT) and Alzheimer's disease (AD) model mice was investigated using minimally invasive two-photon FLIM, with the protein-bound fraction of nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) a2% serving as a metric for mitochondrial metabolic activity. The probe " Ru(BPY)3 " was calibrated to examine the dynamic nature of its phosphorescence lifetime to estimate the partial pressure of oxygen ( pO2 ) in brain vasculature of live animals.
    Approach: Simultaneous two-photon fluorescence and phosphorescence lifetime imaging (2P-FLIM-PLIM) provides a minimally invasive approach to measure the metabolic state in combination with the pO2 in the vascularity of live animals. The metabolic state is obtained via FLIM of NAD(P)H, pO2 via the phosphorescence lifetime of Ru(BPY)3 , an oxygen-sensitive exogenous probe.
    Results: AD mouse cortices exhibit higher level of NAD(P)H a2% and lower level of pO2 compared with WT at anesthetized resting-state. 2P-PLIM investigation reveals that the lower level of pO2 in vascular network Alzheimer's disease (AD) mice cortex indicates increased oxygen consumption in AD.
    Conclusions: The concurrent application of simultaneous 2P-FLIM-PLIM in the mouse brain establishes this dual-modality protocol for the simultaneous assessment of cerebral metabolic alterations using biomarker NAD(P)H and ruthenium-based cerebrovascular oxygen tension measurements. These findings underscore the utility of this multiparametric optical imaging strategy in elucidating the interplay between mitochondrial metabolic dysfunction and impaired brain tissue oxygenation, providing a compelling platform for advancing mechanistic investigations into the neuropathological sequelae of Alzheimer's disease.
    Keywords:  2P-FLIM; 2P-PLIM; Alzheimer’s disease; NAD(P)H; metabolism; oxygen tension; ruthenium
    DOI:  https://doi.org/10.1117/1.NPh.13.3.035008
  5. Metab Brain Dis. 2026 Sep 14. pii: 220. [Epub ahead of print]41(1):
    Significance of NAD anabolism profiles in neurological diseases.
    Abhishek Kumar Mishra, Dipak Kumar, Sakshi Jaiswal, Nitin Mishra, Syed Ibrahim Rizvi.
      Neurons are post-mitotic polarized cells with a higher energy budget which is required to maintain ion gradients, axonal trafficking, firing, and synaptic transmission. The increased cell surface area resulting from the extension of the neuronal membrane and the protrusion of axoplasm from the soma also significantly amplifies neuronal energy demands. To achieve bioenergetic homeostasis, neurons have a higher metabolic rate and engage in continuous NAD production. Biosynthesis of NAD occurs via the enzymatic conversion of tryptophan, and breakdown in NAD biosynthesis leads to neuronal deterioration and the accumulation of tryptophan metabolites in affected brain regions. There exists a good body of evidence linking associations between several neurological disorders and tryptophan metabolites, aberrant expression of NAD biosynthesis enzymes, and polymorphisms in genes encoding enzymes. This review describes the involvement of NAD biosynthetic enzymes in neuropathogenesis and disease. Further, it discusses the association of CNS disorders with various polymorphisms and altered levels of tryptophan metabolites in biofluids, as well as the prognostic value of NAD-associated biomolecules in neurological diseases. Together, the review suggests that quantifying tryptophan-catabolizing enzymes and tryptophan catabolites involved in NAD biosynthesis in biofluids provides a minimally invasive means to monitor neurodegenerative and neuropsychiatric processes. This approach offers a prognostic insight into disease progression, treatment efficacy, and individualized risk assessment.
    Keywords:  Kynurenine metabolites; Kynurenine pathway; NAD; Neurodegenerative diseases; Prognostic biomarkers; Tryptophan
    DOI:  https://doi.org/10.1007/s11011-026-01988-5
  6. Nat Cell Biol. 2026 Sep 15.
    Batten disease protein CLN8 enables a non-canonical phospholipid synthesis pathway.
    Johannes Breithofer, Nermeen Fawzy, Clara Zitta, Martin Tischitz, Dominik Bulfon, Clemens Hofmann, Lennart Hartig, Carina Wagner, Gernot F Grabner, Anita Pirchheim, Achim Lass, Ulrike Taschler, Keira Turner, Kasparas Petkevicius, Ulrich Stelzl, Dagmar Kratky, Rolf Breinbauer, Robert Zimmermann.
      According to text book knowledge, de novo glycerophospholipid (GPL) synthesis begins with the acylation of glycerol-3-phosphate to form phosphatidic acid, the precursor of all other GPLs. Here we describe an alternative GPL synthesis pathway that starts with the acyl-CoA-dependent acylation of glycerophosphoglycerol, resulting in the formation of lysophosphatidylglycerol. The acyltransferase reaction is catalysed by the Batten disease-associated protein ceroid lipofuscinosis neuronal 8 (CLN8). Tracer studies revealed that CLN8-derived lysophosphatidylglycerol is selectively converted into bis(monoacylglycero)phosphate (BMP), a GPL essential for lysosomal lipid homeostasis but not into phosphatidylglycerol or cardiolipin. CLN8-knockout cells and mice cannot utilize glycerophosphoglycerol for BMP synthesis, resulting in BMP deficiency and excess accumulation of phospholipids in lysosomes. The lipid synthesis pathway described herein is relevant for understanding lysosomal lipid metabolism and the pathogenesis of neurodegenerative diseases. BMP deficiency may contribute to or even underlie lysosomal cargo accumulation in certain forms of Batten disease and other lysosomal storage disorders.
    DOI:  https://doi.org/10.1038/s41556-026-02059-8
  7. Geroscience. 2026 Sep 17.
    Age-dependent changes in lipid droplet distribution and vascularization in naked mole rat vs. mouse hippocampus.
    Liv S Krogstad, Markus Augustin Teppen, Harald S Mjønes, Jonathan R Brewer, Thomas Park, Samuel Geiseler, Cecilie Morland.
      The accumulation of lipid droplets in microglia has been reported to increase in response to ageing and age-related diseases like Alzheimer's disease. The present study investigates changes in lipid droplet dynamics with increasing age in the mouse and the similarly sized long-lived rodent, the naked mole rat (Heterocephalus glaber). We show that the naked mole rat contains large amounts of microglial lipid droplets in the CA1 and CA3 region of the hippocampus with an age-dependent increase in the CA3 region. Neuronal lipid droplet size is unaffected by age in the naked mole rat. The mouse hippocampus contains fewer microglial lipid droplets and shows no age-dependent change. However, neuronal lipid droplet size increases with age in the CA3 region in mice. These results could indicate two different ways of regulating lipid accumulation in the brain, where the naked mole rat shuttles their lipids from neurons to microglia to prevent neuronal lipotoxicity and neurodegeneration, while this does not seem to happen in mice. This shuttling of lipids between cells could be a protective mechanism contributing to the high resilience against diseases and damages to the brain seen in the naked mole rat. Additionally, we show that the brain of the naked mole rat has a lower vascularization than the mouse in the dentate hilus, stratum radiatum, and sensory/motor cortex. This could be coupled to the naked mole rats' low metabolism and conforms with its ability to live with low concentrations of oxygen without damage to the brain.
    Keywords:  Ageing; Confocal microscopy; Hippocampus; Lipid droplet; Microglia; Naked mole rat; Vascularization
    DOI:  https://doi.org/10.1007/s11357-026-02548-6
  8. Neurotherapeutics. 2026 Sep 18. pii: S1878-7479(26)00246-1. [Epub ahead of print]23(6): e01076
    PDE5 inhibition restores mitochondrial function and improves neurobehavioral outcomes after repeated mild blast TBI.
    Madison O Kilgore, Shaojing Ye, Felix Oyelami, Alaa Alareidi, Jaycie Gard, Lance A Johnson, Gopal V Velmurugan, W Brad Hubbard.
      Repeated mild traumatic brain injury (rmbTBI) is associated with persistent neurological deficits in military personnel arising from secondary cerebrovascular and metabolic impairments. Critically, there are no FDA-approved therapeutics for rmbTBI. Phosphodiesterase 5 (PDE5) inhibition has been explored in preclinical and clinical TBI studies; however, its exact therapeutic mechanism remains unclear. Recent data demonstrate that PDE5 inhibition can rescue mitochondrial dysfunction. As such, we hypothesized that PDE5 inhibition with sildenafil restores mitochondrial health following rmbTBI, conferring neurobehavioral improvement after rmbTBI. To model rmbTBI, male rats were exposed to two 11 psi blast waves 24 h apart, and daily sildenafil was initiated either 15 min or 8 weeks post-blast to assess subacute and delayed treatment effects. At 7 d post-injury, sildenafil restored rmbTBI-induced reductions in hippocampal expression of PGC-1α, a master regulator of mitochondrial biogenesis. Transcriptomic analysis revealed enrichment of oxidative phosphorylation pathways in sildenafil-treated animals, and metabolomic profiling indicated that rmbTBI results in cortical accumulation of glycolytic intermediates and altered NAD+ redox balance, both attenuated by sildenafil. To assess the mitochondrial signature of brain capillaries after PDE5 inhibition, we show that sildenafil restored mitochondrial bioenergetics in brain capillaries following AAPH-induced oxidative stress and rmbTBI. rmbTBI increased anxiety-like behavior at 3 d and 7 d post-injury, which was partially normalized by sildenafil. At 20 weeks, rmbTBI animals exhibited persistent fear-conditioned behavior, whereas sildenafil facilitated fear extinction. These findings demonstrate that rmbTBI disrupts mitochondrial function and behavior, and that PDE5 inhibition with sildenafil restores these alterations, supporting its potential as a therapeutic intervention for blast-induced TBI.
    Keywords:  Behavior; Blast exposure; Low level blast; Mitochondria; Neurovascular; Sildenafil
    DOI:  https://doi.org/10.1016/j.neurot.2026.e01076
  9. Nat Commun. 2026 09 16. pii: 9647. [Epub ahead of print]17(1):
    Cholesterol maintains the degradative capacity of lysosomes during clearance and recycling of dysfunctional mitochondria.
    Haoning Yang, Koji Matsuhisa, Meng Wei, Wataru Nishi, Dylan Hong Zheng Koh, Aik Yong Sim, Isabelle Bonne, Yasunori Saheki.
      Efficient clearance and recycling of dysfunctional mitochondria through the robust catabolic activity of lysosomes are essential for cellular health. However, how membrane lipids contribute to maintaining the degradative capacity of lysosomes remains poorly understood. Here, we show that cholesterol plays a critical role in preserving the functional integrity of degradative lysosomes. Clearance of damaged mitochondria by degradative lysosomes is tightly coupled with the acute accumulation of phosphatidylinositol 4-phosphate (PI4P) on the lysosomal surface via PI4KIIα activity. This PI4P accumulation activates oxysterol-binding protein (OSBP)-mediated cholesterol transport from the endoplasmic reticulum (ER) to lysosomal membranes. The resulting efflux of cholesterol from the ER activates sterol regulatory element-binding protein 2 (SREBP-2), enhancing cholesterol production. Sustained cholesterol accumulation on lysosomal membranes maintains lysosomal acidity and membrane integrity for efficient mitochondrial degradation. This degradation process then leads to the release of free fatty acids and their recycling and storage through the formation of DGAT1-dependent lipid droplets. These findings uncover a key phosphoinositide-regulated cholesterol transport pathway that promotes the clearance and recycling of dysfunctional mitochondria, a process whose impairment is closely linked to neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-026-77423-1
  10. Cells. 2026 Aug 29. pii: 1571. [Epub ahead of print]15(17):
    Lactate Metabolism and Signaling in Amyotrophic Lateral Sclerosis.
    Xiaonan Ma, Jinmeng Liu, Yingjun Guan, Chunjie Xu, Mu Li, Xue Zhang, Zongze Li, Lanli Zhang, Xuemei Wang, Haoyun Zhang, Yanchun Chen.
      Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease characterized by the selective degeneration of upper and lower motor neurons (MNs). Although the specific pathogenesis of ALS is not yet fully understood, there is increasing evidence that abnormal energy metabolism plays a key role in the onset and progression of the disease. Lactate has traditionally been considered a metabolic by-product of glycolysis and has received increasing attention in recent years. Research has shown that lactate is not only an important energy substrate but also a signaling molecule that regulates a variety of physiological processes, including neuron-glia metabolic coupling, neuroprotection and inflammatory responses. In ALS, abnormalities in lactate metabolism, dysfunction of the lactate shuttle, and dysregulation of lactate-related signaling pathways may jointly lead to neuronal energy deficits and increased neuroinflammation, thereby promoting MN degeneration. This review summarizes the latest advances in lactate metabolism and lactate-mediated signaling in ALS, with particular emphasis on their roles in neuronal energy regulation, neuroprotection and inflammatory regulation. In addition, we also discuss potential therapeutic strategies for lactate metabolism and its related pathways, aiming to provide new insights into the pathogenesis of ALS and the development of treatment methods for lactate-related metabolism.
    Keywords:  amyotrophic lateral sclerosis; lactate metabolism; lactate signaling; lactylation; therapy
    DOI:  https://doi.org/10.3390/cells15171571
  11. J Alzheimers Dis. 2026 Sep 16. 13872877261487394
    L-serine-enriched diet restores impaired adult neurogenesis in the hippocampus of 3xTg-AD mice.
    Brainbank Neuro-CEB Neuropathology Network 5
      BackgroundAltered adult neurogenesis occurs in Alzheimer's disease (AD) in humans and rodent models, though the mechanisms remain unclear. L-serine, a non-essential amino acid critical for cell proliferation and survival, is produced by neuroepithelial cells and radial glia in the developing brain, and by astrocytes and neural precursors in the adult brain. Its production is altered in AD, particularly in the hippocampus.ObjectiveTo determine whether reduced L-serine availability contributes to impaired adult neurogenesis in AD.MethodsWe examined the expression of phosphoglycerate dehydrogenase (PHGDH), an enzyme in L-serine biosynthesis, in neural stem cells (NSCs) of mouse and human dentate gyrus (DG). Adult neurogenesis was assessed by quantifying proliferating neural precursors and immature neurons in 7- and 12-month-old 3xTg-AD mice and age-matched controls. Mice received an L-serine-enriched diet for 4 or 8 months, after which plasma serine levels, neurogenesis markers, and amyloid pathology were evaluated.ResultsPHGDH was expressed by NSCs in the mouse DG and by cells in the subgranular zone (SGZ) of the human DG showing radial morphology typical of rodent NSCs. Twelve-month-old 3xTg-AD mice showed a significant reduction in proliferating (PCNA-positive) precursors and immature (DCX-positive) neurons in the DG relative to controls. L-serine supplementation significantly raised plasma L- and D-serine levels and partially rescued neurogenesis deficits in 3xTg-AD mice, without affecting amyloid pathology.ConclusionsWe suggest that impairment of L-serine metabolism and the resulting reduction in D-serine availability contributes to impaired adult neurogenesis, potentially via reduced survival of newborn neurons in the DG of 3xTg-AD mice.
    Keywords:  Alzheimer's disease; L-serine; adult neurogenesis; energy metabolism; glia; hippocampus; neural precursors
    DOI:  https://doi.org/10.1177/13872877261487394
  12. Elife. 2026 Sep 18. pii: RP104055. [Epub ahead of print]13
    Defective neuronal differentiation in Lowe syndrome is associated with mitochondrial dysfunction and impaired cilia-related Sonic Hedgehog signaling.
    Grzegorz Walkiewicz, Siyu Chen, Chienhui Lo, Jingyu Zhao, Zhiquan Liu, Biao Wang, Qing Wang, Tia J Kowal, Benjamin Lawson, Yang Sun.
      Human brain development requires tight coordination of metabolic and signaling pathways. Lowe syndrome (LS) is a recessive X-linked disorder characterized by proximal tubular renal disease, congenital cataracts, glaucoma, and neurodevelopmental delays. While LS results from mutations in the OCRL gene, which encodes an inositol polyphosphate 5-phosphatase, the cellular mechanisms driving neuronal dysfunction remain poorly understood. In this study, using patient-derived iPSC neurons, an Ocrl knockout mouse model, and an independent zebrafish OCRL-deficient model, we identified mitochondrial dysfunction as a conserved phenotype of OCRL loss across species. Collectively, our findings showed that OCRL deficiency leads to reduced mitochondrial activity, decreased mtDNA levels, reduced mitochondrial content (TOM20), and increased oxidative stress. We further showed that OCRL-deficient neural cells exhibited an altered balance of neuronal versus astrocytic differentiation, rather than a defect in neurogenesis. Additionally, we observed impaired Sonic Hedgehog (Shh) signaling and ciliary homeostasis. Thus, our findings support a model in which OCRL deficiency is associated with mitochondrial dysfunction, increased oxidative stress, altered neural lineage balance, and reduced Hedgehog pathway activity, providing a framework for understanding these interconnected phenotypes.
    Keywords:  Lowe syndrome; ROS; cell biology; cilia formation; human; mitochondria; mouse; neuronal differentiation; oxidative stress; zebrafish
    DOI:  https://doi.org/10.7554/eLife.104055
  13. Stem Cell Reports. 2026 Sep 17. pii: S2213-6711(26)00291-2. [Epub ahead of print] 103080
    PEX11β controls early neural progenitor fate through regulation of peroxisomal fission and lipid metabolism.
    C Bodnya, R P Theart, M E Colley, J M Spraggins, V Gama.
      Peroxisomes are metabolic organelles that undergo fission to maintain peroxisome number for lipid homeostasis and cellular function. The peroxisomal fission machinery is shared with mitochondria, and although mitochondrial fission regulates neural cell fate decisions during human neurogenesis, it remains unclear whether peroxisomal fission independently influences human neural development. PEX11β selectively regulates peroxisomal fission by promoting membrane deformation, elongation, and downstream fission factor recruitment. To uncouple mitochondrial and peroxisomal fission in early human neurogenesis, we generated PEX11β knockout iPSCs and tracked differentiation into neural progenitors and neural rosettes. At the cellular level, perturbing PEX11β selectively impaired peroxisomal lipid metabolism, characterized by reduced ether-linked phospholipids. At the tissue level, PEX11β deficiency altered neural rosette architecture, resulting in enlarged central lumens and expanded neural progenitor populations. This human neural model uncouples mitochondrial and peroxisomal fission and positions PEX11β as a distinct regulator of lipid metabolism and neural progenitor fate during human neurogenesis.
    Keywords:  DRP1; PEX11β; fission; induced pluripotent stem cells; neural progenitor cells; neurogenesis; peroxisomes
    DOI:  https://doi.org/10.1016/j.stemcr.2026.103080
  14. Nat Cell Biol. 2026 Sep 15.
    The Batten disease protein CLN8 is a stereospecific acyltransferase in bis(monoacylglycero)phosphate biosynthesis.
    Pradeep K Sheokand, Denis Lacabanne, Andrew M James, Stefania Della Vecchia, Jonathan J Ruprecht, Joris van der Kleij, Keira Turner, Jessica Müller-Niva, Miia H Salo, Benjamin Jenkins, Susannah K Leese, Nidhi Juneja, Chak Shun Yu, Clarissa D Booth, Martin S King, Johanna Uusimaa, Jill M Weimer, Albert Koulman, Reetta Hinttala, Filippo M Santorelli, Maria Marchese, Michael P Murphy, Edmund R S Kunji, Kasparas Petkevicius.
      Loss-of-function mutations in the endoplasmic reticulum membrane protein CLN8 cause Batten disease, a neurodegenerative lysosomal storage disorder. CLN8 acts with the lysosomal enzyme CLN5 to produce bis(monoacylglycero)phosphate (BMP), a signature lysosomal phospholipid with unique S,S stereochemistry. However, the role of CLN8 in this pathway has remained unclear. Here we establish that CLN8 is a glycerophosphoglycerol acyltransferase that catalyses the stereospecific acylation of S,S-glycerophosphoglycerol to generate S,S-lysophosphatidylglycerol, the CLN5 substrate in BMP synthesis. Cryo-electron microscopy structures define the CLN8 active site and support a ping-pong acyl transfer mechanism. Batten disease mutations impair CLN8 enzymatic activity and abolish BMP production in mice. Exogenous S,S-lysophosphatidylglycerol, but not the R,S stereoisomer, restores BMP synthesis in CLN8-deficient cells and mice and improves neurological phenotypes in cln8 mutant zebrafish. These findings define the function of CLN8, explain the biochemical basis of CLN8 Batten disease and establish BMP precursor supplementation as a proof-of-concept therapeutic strategy.
    DOI:  https://doi.org/10.1038/s41556-026-02061-0
  15. Brain. 2026 Sep 16. pii: awag311. [Epub ahead of print]
    The longevity gene APOE2 enhances pericyte function and reduces lipid droplets.
    Rais Reskiawan A Kadir, Joanna Bons, Genesis Vega Hormazabal, Prasanna Vadhana Ashok Kumaar, Cristian Gerónimo-Olvera, Kizito-Tshitoko Tshilenge, Philippe Pihán, Carlos Galicia Aguirre, Kevin Schneider, Andrea Roberts, Benjamin D Ambrose, Chad Lerner, Nicholas A Devanney, Anja M Sandholm, Mikayla Hady, Sydney Alderfer, Claudio Hetz, David Furman, Akos A Gerencser, Eric Verdin, Birgit Schilling, Lisa M Ellerby.
      Pericytes are critical for maintaining blood-brain barrier (BBB) integrity and have emerged as key contributors to Alzheimer's disease (AD) pathogenesis. Although the apolipoprotein E2 (APOE2) allele is associated with reduced AD risk and increased longevity, its impact on pericyte function is unclear. We measured pericyte density in the brains of humanized APOE2, APOE3, and APOE4 knock-in mice and found that APOE2 mice revealed increased pericyte markers and enhanced BBB integrity. To uncover the underlying mechanisms, we used CRISPR/Cas9 editing to generate isogenic human iPSC-derived pericytes carrying APOE2, APOE3, or APOE4 alleles. All lines expressed pericyte markers in an APOE allele-dependent levels. Using a human in vitro BBB model incorporating endothelial cells, astrocytes, and genotype-specific pericytes, we found that APOE2 pericytes provided greater overall cerebral barrier integrity. Further, APOE2 pericytes exhibited increased resistance to senescence and reduced amyloid-β accumulation. Using unbiased proteomic profiling to understand these cellular phenotypes, we found significant alterations in lipid metabolism-related proteins. Untargeted lipidomic analysis confirmed a genotype-specific lipid signature, observing reduced phospholipids and increased triglycerides in APOE2 pericytes. Interestingly, APOE2 pericytes showed lower lipid droplet (LD) accumulation. Proteomics analysis revealed increased expression of proteins involved in lipid degradation, β-oxidation, and lipid transport, suggesting more efficient lipid processing. Notably, recombinant APOE2 treatment effectively rescued pericyte function and mitigated LD accumulation in APOE3 and APOE4 pericytes. Collectively, these findings demonstrate that APOE2 expression supports pericyte functionality through increased lipid processing, providing mechanistic insight into the cerebrovascular protective effects of APOE2 in pericytes. These findings could be translated into novel therapies aimed at enhancing pericyte function and lipid metabolism, particularly in individuals at risk for neurodegenerative diseases.
    Keywords:  APOE; Alzheimer’s disease; blood–brain barrier; lipidomics; longevity; proteomics; senescence
    DOI:  https://doi.org/10.1093/brain/awag311
  16. IBRO Neurosci Rep. 2026 Dec;21 747-753
    PET-MRI effects of N-acetylcysteine in patients with multiple sclerosis.
    Daniel A Monti, Sahar Darabi Monadi, Feroze B Mohamed, Mahdi Alizadeh, George Zabrecky, Nancy Wintering, Monisha Gupta, Alicia Steinmetz, Daniel Kremens, Anthony J Bazzan, Andrew B Newberg.
       Background: The purpose of this study was to explore if administration of N-acetylcysteine (NAC) in patients with multiple sclerosis (MS) resulted in altered neurophysiological function as determined by the combination of functional connectivity (FC) based on resting Blood Oxygen Level Dependent (BOLD) fMRI and cerebral glucose metabolism using Fluorodeoxyglucose Positron Emission Tomography (FDG PET) and whether those changes were associated with improvements in symptoms.
    Methods: Thirty-six patients with mild to moderate MS were randomized to either NAC plus standard of care, or standard of care only. The experimental group received NAC intravenously (50 mg/kg) once per week and orally (500 mg 2x/day) the other six days. Patients in both groups were evaluated initially and after 4 ± 2 months on an integrated PET-MRI platform with resting BOLD fMRI and FDG PET. Clinical symptom questionnaires were also completed at both time points.
    Results: The FC data showed significant differences in several brain regions including the inferior frontal gyrus, inferior temporal gyrus, inferior parietal gyrus, insula, cerebellum, and brain stem in the MS group after treatment with NAC. FDG PET demonstrated increased cerebral glucose metabolism in several of these structures including the inferior frontal gyrus and inferior temporal gyrus. Self-reported scores related to cognition and attention significantly correlated with these neurophysiological changes in the NAC group compared to controls.
    Conclusions: The results of this study suggest that NAC administration alters resting functional connectivity along with cerebral glucose metabolism in MS patients, and this is associated with qualitative improvements in cognition and attention.
    Keywords:  Antioxidant; Cerebral metabolism; Cognition; FMRI; Functional connectivity; Multiple sclerosis; N-acetylcysteine; NAC; PET-MRI; Positron Emission Tomography
    DOI:  https://doi.org/10.1016/j.ibneur.2026.08.014
  17. iScience. 2026 Oct 16. 29(10): 117487
    Endothelial SLC38A2 controls brain D-serine homeostasis and synapse development.
    Akshay K Tiwari, Ankita Lahkar, Clara Sajrawi, Yara Hussein, Adam Majcher, Stephane Bonelli, Bella Agranovich, Ifat Abramovich, Shani Stern, Farrukh A Chaudhry, Thorsten Hornemann, Inna Radzishevsky, Herman Wolosker.
      L-serine is a precursor for the synthesis of the neuromodulator D-serine, glycine, and lipids. Contrary to the prevailing view that brain L-serine is exclusively derived from de novo synthesis, we demonstrate that dietary L-serine is required to maintain brain L-serine levels and prevents the formation of neurotoxic 1-deoxysphingolipids. We identified SLC38A2 as an L-serine transporter at the blood-brain barrier (BBB) that mediates the influx of circulating L-serine to the brain. Endothelial-selective Slc38a2 conditional knockout (Slc38a2-cKO) decreased in vivo blood-to-brain L-serine influx and selectively lowered hippocampal L-serine and D-serine in mouse pups. Immunoelectron microscopy demonstrated that SLC38A2 is localized to both the luminal and abluminal endothelial membranes. Slc38a2-cKO pups exhibited ultrastructural defects at excitatory synapses, including reduced synaptic vesicle cluster size and decreased postsynaptic density area. SLC38A2 inhibition may be beneficial for limiting D-serine accumulation in conditions with pathologically elevated L- or D-serine levels, such as traumatic brain injury and epilepsy.
    Keywords:  D-serine; amino acid transport; blood-brain barrier; serine
    DOI:  https://doi.org/10.1016/j.isci.2026.117487
  18. Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2616684123
    Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum.
    Baolong Xia, Myeonghoon Han, Isaac Park, Norbert Perrimon.
      Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.
    Keywords:  SREBP; de novo lipogenesis; lysosomal enzyme transport; protein myristoylation; proximity labeling
    DOI:  https://doi.org/10.1073/pnas.2616684123
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