bims-medebr 2025-01-05 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2025–01–05
nine papers selected by
Regina F. Fernández, Johns Hopkins University

Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis.
Glial Biologist's Guide to Mass Spectrometry-Based Lipidomics: A Tutorial From Sample Preparation to Data Analysis.
Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration.
Exogenous ketone bodies and the ketogenic diet as a treatment option for neurodevelopmental disorders.
Immunometabolism In Brain Aging and Neurodegeneration: Bridging Metabolic Pathways and Immune Responses.
Exploring fatty acid metabolism in Alzheimer's disease: the key role of CPT1A.
Dodecyl creatine ester, a promising treatment to deliver creatine to neurons, achieves pharmacology efficacy in creatine transporter deficiency.
ATP5J regulates microglial activation via mitochondrial dysfunction, exacerbating neuroinflammation in intracerebral hemorrhage.
TNFAIP3 affects ferroptosis after traumatic brain injury by affecting the deubiquitination and ubiquitination pathways of the HMOX1 protein and ACSL3 TNFAIP3 affects ferroptosis after traumatic brain injury.

Sci Rep. 2025 Jan 02. 15(1): 325

Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis.

Raffaele Pastore, Lihang Yao, Nathan Hatcher, Martin Helley, Janet Brownlees, Radha Desai.

Dysfunction of the endo-lysosomal intracellular Cholesterol transporter 2 protein (NPC2) leads to the onset of Niemann-Pick Disease Type C (NPC), a lysosomal storage disorder. Metabolic and homeostatic mechanisms are disrupted in lysosomal storage disorders (LSDs) hence we characterized a cellular model of NPC2 knock out, to assess alterations in organellar function and inter-organellar crosstalk between mitochondria and lysosomes. We performed characterization of lipid alterations and confirmed altered lysosomal morphology, but no overt changes in oxidative stress markers. Using several techniques, we demonstrated that contacts between mitochondria and late endosomes/lysosomes are reduced in NPC2-/- HEK cells, we observed that the acidic compartments are swollen and lipid dense. Quantification of endogenous lipids in HEKNPC2-/- cells by mass spectrometry reveals accumulation of lipid species indicative of sphingolipid metabolic dysregulation within the lysosome. Specifically, HEK NPC2-/- cells exhibit marked elevation of glucosylsphingosine and glucosylceramides, substrates of beta glucocerebroside (GBA), as well as accumulation of sphingosine and sphingomyelins. Our studies suggest an involvement of NPC2 in the formation of contact sites between mitochondria and lysosomes and support the hypothesis of a role for NPC2 in the endo-lysosomal trafficking pathway and dynamic organellar crosstalk.

DOI: https://doi.org/10.1038/s41598-024-83460-x
Glia. 2025 Jan 03.

Glial Biologist's Guide to Mass Spectrometry-Based Lipidomics: A Tutorial From Sample Preparation to Data Analysis.

Caitlin E Randolph, Katherine A Walker, Ruilin Yu, Connor Beveridge, Palak Manchanda, Gaurav Chopra.

  Neurological diseases are associated with disruptions in the brain lipidome that are becoming central to disease pathogenesis. Traditionally perceived as static structural support in membranes, lipids are now known to be actively involved in cellular signaling, energy metabolism, and other cellular activities involving membrane curvature, fluidity, fusion or fission. Glia are critical in the development, health, and function of the brain, and glial regulation plays a major role in disease. The major pathways of glial dysregulation related to function are associated with downstream products of metabolism including lipids. Taking advantage of significant innovations and technical advancements in instrumentation, lipidomics has emerged as a popular omics discipline, serving as the prevailing approach to comprehensively define metabolic alterations associated with organismal development, damage or disease. A key technological platform for lipidomics studies is mass spectrometry (MS), as it affords large-scale profiling of complex biological samples. However, as MS-based techniques are often refined and advanced, the relative comfort level among biologists with this instrumentation has not followed suit. In this review, we aim to highlight the importance of the study of glial lipids and to provide a concise record of best practices and steps for MS-based lipidomics. Specifically, we outline procedures for glia lipidomics workflows ranging from sample collection and extraction to mass spectrometric analysis to data interpretation. To ensure these approaches are more accessible, this tutorial aims to familiarize glia biologists with sample handling and analysis techniques for MS-based lipidomics, and to guide non-experts toward generating high quality lipidomics data.

Keywords:  glial lipidomics; lipid identification; lipidomics data analysis; lipids in neurological disease; mass spectrometry‐based lipidomics; sample preparation

DOI:  https://doi.org/10.1002/glia.24665
Sci Transl Med. 2025 Jan;17(779): eadp5247

Lipidomic profiling of mouse brain and human neuron cultures reveals a role for Mboat7 in mTOR-dependent neuronal migration.

Isaac Tang, Ashna Nisal, Alex Reed, Timothy B Ware, Anide Johansen, Maha S Zaki, Benjamin F Cravatt, Joseph G Gleeson.

Mutations in lipid regulator genes are a frequent cause of autism spectrum disorder, including those regulating phosphatidylinositol (PI) and phosphoinositide 3-kinase signaling. MBOAT7 encodes a key acyltransferase in PI synthesis and is mutated in an autism-related condition with neurodevelopmental delay and epilepsy. Using liquid chromatography-tandem mass spectrometry, we analyzed the PI-associated glycerolipidome in mice and humans during neurodevelopment and found dynamic regulation at times corresponding to neural apoptosis in the brains of Mboat7 knockout mice. Mboat7 function was necessary for polyunsaturated lipid synthesis and cortical neural migration, and loss resulted in massive accumulation of the precursor lysophosphatidylinositol and hyperactive mTOR signaling. Inhibiting mTOR signaling rescued migration defects. Our findings demonstrate roles for lipid remodeling during neurodevelopment and implicate lipid regulation in neuronal migration, revealing potential paths to treatment for MBOAT7 deficiency.

DOI: https://doi.org/10.1126/scitranslmed.adp5247
Front Nutr. 2024 ;11 1485280

Exogenous ketone bodies and the ketogenic diet as a treatment option for neurodevelopmental disorders.

Naomi Elyse Omori, Mantas Kazimieras Malys, Geoffrey Woo, Latt Mansor.

   Background: Despite being the most prevalent neurodevelopmental disorders, there are comparatively few treatment options available to patients presenting with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD). The ketogenic diet has historically shown therapeutic utility in treating refractory epilepsy, an adjacent neuropsychiatric condition, in children, adolescents and adults. The following review explores preclinical and clinical literature focusing on the therapeutic potential of the ketogenic diet and exogenous ketone body supplementation in treating common neurodevelopmental disorders.
Method: A narrative review of extant literature was conducted across the domains of perinatal nutrition, ASD, and ADHD. Preclinical and clinical studies focusing on the effect of either the ketogenic diet or exogenous ketone supplementation as a treatment option were included for review.
Results: 14 preclinical and 10 clinical studies were included for discussion. Data supporting the use of a ketogenic intervention for neurodevelopmental disorders is mixed. High heterogeneity in study design was noted for preclinical models, ketogenic intervention, and outcomes measured.
Conclusion: Studies evaluating ketogenic interventions for neurodevelopmental disorders remain in their infancy in terms of both the depth and scope of available literature. The safety and tolerability of ketogenic diets and supplements means there would be value in exploring their effectiveness further in clinical studies.

Keywords:  ADHD; ASD; BHB; autism; ketogenic diet; ketone bodies; ketones; neurodevelopment

DOI:  https://doi.org/10.3389/fnut.2024.1485280
Aging Dis. 2024 Dec 30.

Immunometabolism In Brain Aging and Neurodegeneration: Bridging Metabolic Pathways and Immune Responses.

Shokofeh Rahimpour, Briana L Clary, Sanaz Nasoohi, Yohanna S Berhanu, Candice M Brown.

The complex set of interactions between the immune system and metabolism, known as immunometabolism, has emerged as a critical regulator of disease outcomes in the central nervous system. Numerous studies have linked metabolic disturbances to impaired immune responses in brain aging, neurodegenerative disorders, and brain injury. In this review, we will discuss how disruptions in brain immunometabolism balance contribute to the pathophysiology of brain dysfunction. The first part of the review summarizes the contributions of critical immune cell populations such as microglia, astrocytes, and infiltrating immune cells in mediating inflammation and metabolism in CNS disorders. The remainder of the review addresses the impact of metabolic changes on immune cell activation and disease progression in brain aging, Alzheimer's disease, Parkinson's disease, multiple sclerosis, stroke, spinal cord injury, and traumatic brain injury. Furthermore, we also address the therapeutic potential of targeting immunometabolic pathways to reduce neuroinflammation and slow disease progression. By focusing on the interactions among brain immune cells and the metabolic mechanisms they recruit in disease, we present a comprehensive overview of brain immunometabolism in human health and disease.

DOI: https://doi.org/10.14336/AD.2024.1293
Sci Rep. 2024 Dec 28. 14(1): 31483

Exploring fatty acid metabolism in Alzheimer's disease: the key role of CPT1A.

Yanxiu Ju, Songtao Li, Xiangyi Kong, Qing Zhao.

Alzheimer's disease (AD) is a severe neurodegenerative disease, and the most common type of dementia, with symptoms of progressive cognitive dysfunction and behavioral impairment. Studying the pathogenesis of AD and exploring new targets for the prevention and treatment of AD is a very worthwhile challenge. Accumulating evidence has highlighted the effects of fatty acid metabolism on AD. In this study, fatty acid metabolism was used as an entry point to understand the pathogenesis of AD and identify new targets. After identifying differentially expressed genes, multiple machine learning algorithms, carnitine palmitoyltransferase 1 A (CPT1A) was identified as the key gene for fatty acid metabolism in AD. Further single nucleus RNA sequencing analysis were performed, and the GSEA results showed that the fatty acid β-oxidation pathway was enriched only in astrocytes, and the fatty acid β-oxidation pathway was down-regulated in the AD astrocytes compared to the CN astrocytes, while CPT1A was specifically downregulated in astrocytes of AD, which was confirmed in vitro experiment subsequently, and decreased expression level of CPT1A would lead to abnormal lipid metabolism, which shapes astrocyte reactivity and injury, neuroinflammatory, and thus affects AD pathogenesis. Our findings report the involvement of CPT1A in AD. We confirm that the primary role of astrocytes for fatty acid β-oxidation, and CPT1A is localized in astrocytes. Downregulated CPT1A could be a novel potential target for the prevention and treatment of AD. Our study provides strong evidence for the involvement of fatty acid metabolism in the pathogenesis of AD.

DOI: https://doi.org/10.1038/s41598-024-82999-z
Eur J Med Chem. 2024 Dec 20. pii: S0223-5234(24)01077-8. [Epub ahead of print]284 117195

Dodecyl creatine ester, a promising treatment to deliver creatine to neurons, achieves pharmacology efficacy in creatine transporter deficiency.

Clémence Disdier, Clara Lhotellier, Anne-Cécile Guyot, Narciso Costa, Frédéric Théodoro, Alain Pruvost, Matthew R Skelton, Thomas Joudinaud, Aloïse Mabondzo, Henri Bénech.

  Dodecyl creatine ester (DCE) is a creatine prodrug currently developed for brain diseases, including creatine transporter deficiency (CTD), an incurable rare genetic disease. A dual strategy combining a prodrug to bypass the non-functional creatine transporter and its delivery via the nose-to-brain pathway has been proposed to replenish creatine levels in cerebral cells, particularly in neurons of CTD patients. In vitro and in vivo studies in various animal models, including wild-type non-human primates and creatine transporter deficient mice, show that formulated DCE, when administered intranasally, achieves significant cerebral distribution up to the target cells, the neurons, and modulates the expression of neuronal markers related to cognitive function at doses intended for patients. These compelling results contribute to a better understanding of the pharmacokinetics and pharmacodynamics of DCE after nasal administration, with a particular focus on the crucial role of the nose-to-brain pathway in DCE distribution.

Keywords:  Creatine; Creatine transporter deficiency; Intranasal drug administration; Non-human primate; Nose-to-brain drug delivery; Prodrug; Slc6a8 deficient mice

DOI:  https://doi.org/10.1016/j.ejmech.2024.117195
Front Immunol. 2024 ;15 1509370

ATP5J regulates microglial activation via mitochondrial dysfunction, exacerbating neuroinflammation in intracerebral hemorrhage.

Naixin Ren, Hutao Zhang, Tao Li, Huafang Ji, Zhen Zhang, He Wu.

  Microglial-mediated neuroinflammation is crucial in the pathophysiological mechanisms of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). Mitochondria are central regulators of inflammation, influencing key pathways such as alternative splicing, and play a critical role in cell differentiation and function. Mitochondrial ATP synthase coupling factor 6 (ATP5J) participates in various pathological processes, such as cell proliferation, migration, and inflammation. However, the role of ATP5J in microglial activation and neuroinflammation post-ICH is poorly understood. This study aimed to investigate the effects of ATP5J on microglial activation and subsequent neuroinflammation in ICH and to elucidate the underlying mechanisms. We observed that ATP5J was upregulated in microglia after ICH. AAV9-mediated ATP5J overexpression worsened neurobehavioral deficits, disrupted the blood-brain barrier, and increased brain water content in ICH mice. Conversely, ATP5J knockdown ameliorated these effects. ATP5J overexpression also intensified microglial activation, neuronal apoptosis, and inflammatory responses in surrounding tissues post-ICH. ATP5J impaired microglial dynamics and reduced the proliferation and migration of microglia to injury sites. We used oxyhemoglobin (OxyHb) to stimulate BV2 cells and model ICH in vitro. Further in vitro studies showed that ATP5J overexpression enhanced OxyHb-induced microglial functional transformation. Mechanistically, ATP5J silencing reversed dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1) upregulation in microglia post-OxyHb induction; reduced mitochondrial overdivision, excessive mitochondrial permeability transition pore opening, and reactive oxygen species production; restored normal mitochondrial ridge morphology; and partially restored mitochondrial respiratory electron transport chain activity. ATP5J silencing further alleviated OxyHb-induced mitochondrial dysfunction by regulating mitochondrial metabolism. Our results indicate that ATP5J is a key factor in regulating microglial functional transformation post-ICH by modulating mitochondrial dysfunction and metabolism, thereby positively regulate neuroinflammation. By inhibiting ATP5J, SBI following ICH could be prevented. Therefore, ATP5J could be a candidate for molecular and therapeutic target exploration to alleviate neuroinflammation post-ICH.

Keywords:  ATP5J; intracerebral hemorrhage; microglia; mitochondrial reprogramming; secondary brain injury

DOI:  https://doi.org/10.3389/fimmu.2024.1509370
Free Radic Biol Med. 2024 Dec 30. pii: S0891-5849(24)01157-2. [Epub ahead of print]

TNFAIP3 affects ferroptosis after traumatic brain injury by affecting the deubiquitination and ubiquitination pathways of the HMOX1 protein and ACSL3 TNFAIP3 affects ferroptosis after traumatic brain injury.

Lin Zhou, Lei Li, Jinghao Yang, Maierdan Mansuer, Xianyu Deng, Yida Wang, Hui Ren, Daming Cui, Yang Jiang, Liang Gao.

  The occurrence and progression of traumatic brain injury involve a complex process. The pathophysiological mechanisms triggered by neuronal damage include various forms of programmed cell death, including ferroptosis. We observed upregulation of TNFAIP3 in mice after traumatic brain injury. Overexpression of TNFAIP3 inhibits HT-22 proliferation and cell viability through ferroptosis. Mechanistically, TNFAIP3 interacts with the HMOX1 protein and promotes its stability through the deubiquitination pathway. Additionally, TNFAIP3 can enhance lipoperoxidation, mitochondrial damage, and neuronal cell death by promoting ACSL3 degradation via NEDD4-mediated ubiquitination. Mice injected with AAV-shTNFAIP3 exhibited reduced neuronal degeneration and improved motor and cognitive function following cortical impact injury. In conclusion, our findings demonstrate that TNFAIP3 deficiency inhibits neuronal cell ferroptosis and ameliorates cognitive impairment caused by traumatic brain injury and demonstrate its potential applicability in the treatment of traumatic brain injury.

Keywords:  TNFAIP3; Traumatic brain injury; ferroptosis; ubiquitination

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.048