bims-medebr 2024-01-07 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–01–07
sixteen papers selected by
Regina F. Fernández, Johns Hopkins University

Astrocytes drive divergent metabolic gene expression in humans and chimpanzees.
Gestational Diabetes Mellitus Remodels the Fetal Brain Fatty Acid Profile through Placenta-Brain Lipid Axis in C57BL/6J Mice.
Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development.
Severe central nervous system demyelination in Sanfilippo disease.
Comparing Brain and Blood Lipidome Changes following Single and Repetitive Mild Traumatic Brain Injury in Rats.
SMPD4 mediated sphingolipid metabolism regulates brain and primary cilia development.
Over-expression of N-acetylaspartate synthase exacerbates pathological energetic deficit and accelerates cognitive decline in the 5xFAD mouse.
Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics.
Ascorbic acid and its transporter SVCT2, affect radial glia cells differentiation in postnatal stages.
Isolation and Lipidomic Profiling of Neuronal Lipid Droplets: Unveiling the Lipid Landscape for insights into Neurodegenerative Disorders.
Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.
Modulation of beta-hydroxybutyrate in traumatic brain injury.
The neuropsychopharmacology of acetyl-L-carnitine (LAC): basic, translational and therapeutic implications.
Monitoring lipid alterations in Drosophila heads in an amyotrophic lateral sclerosis model with time-of-flight secondary ion mass spectrometry.
Expression of ceramide synthases in mice and their roles in regulating acyl-chain sphingolipids: A framework for baseline levels and future implications in aging and disease.
Low C0 and normal C16 and C18:1 masking the diagnosis of carnitine palmitoyltransferase II deficiency including a novel CPT2 variant: A case report.

Genome Biol Evol. 2023 Dec 30. pii: evad239. [Epub ahead of print]

Astrocytes drive divergent metabolic gene expression in humans and chimpanzees.

Trisha M Zintel, Jason Pizzollo, Christopher G Claypool, Courtney C Babbitt.

  The human brain utilizes ∼ 20% of all of the body's metabolic resources, while chimpanzee brains use less than 10%. Although previous work shows significant differences in metabolic gene expression between the brains of primates, we have yet to fully resolve the contribution of distinct brain cell types. To investigate cell-type specific interspecies differences in brain gene expression, we conducted RNA-Seq on neural progenitor cells (NPCs), neurons, and astrocytes generated from induced pluripotent stem cells (iPSCs) from humans and chimpanzees. Interspecies differential expression (DE) analyses revealed that twice as many genes exhibit DE in astrocytes (12.2% of all genes expressed) than neurons (5.8%). Pathway enrichment analyses determined that astrocytes, rather than neurons, diverged in expression of glucose and lactate transmembrane transport, as well as pyruvate processing and oxidative phosphorylation. These findings suggest that astrocytes may have contributed significantly to the evolution of greater brain glucose metabolism with proximity to humans.

Keywords:  astrocytes; brain; evolution; genomics; metabolism; neurons

DOI:  https://doi.org/10.1093/gbe/evad239
J Nutr. 2023 Dec 28. pii: S0022-3166(23)72835-6. [Epub ahead of print]

Gestational Diabetes Mellitus Remodels the Fetal Brain Fatty Acid Profile through Placenta-Brain Lipid Axis in C57BL/6J Mice.

Hai-Tao Yu, Jia-Yu Gong, Wen-Hui Xu, Yi-Ru Chen, Yue-Ting Li, Yi-Fei Chen, Guo-Liang Liu, Hai-Ying Zhang, Lin Xie.

   BACKGROUND: Polyunsaturated fatty acids (PUFAs), especially docosahexaenoic acid (DHA), are critical for proper fetal brain growth and development. Gestational diabetes mellitus (GDM) could affect maternal-fetal fatty acid metabolism.
OBJECTIVE: This study explore the effect of GDM and high-fat (HF) diet on the DHA transport signaling pathway in the placenta-brain axis and fatty acid levels in the fetal brain.
METHODS: Insulin receptor antagonist (S961) and HF diet were used to establish an animal model of GDM. Eighty female C57BL/6J mice were randomly divided into Control (CON), GDM, HF, and HF+GDM groups. The fatty acid profiles of the maternal liver and fetal brain were analyzed by gas chromatography (GC). Additionally, we analyzed the protein levels of maternal liver fatty acid desaturase (FADS1/3), elongase (ELOVL2/5) and the regulatory factor SREBP-1c, and the DHA transport signaling pathway (Wnt3/β-catenin/MFSD2a) of the placenta and fetal brain using western blotting.
RESULTS: GDM promoted the decrease of maternal liver ELOVL2, ELOVL5, and SREBP-1c. Accordingly, we observed a significant decrease in the level of maternal liver arachidonic acid (AA), DHA, total n-3 PUFA and n-6 PUFA induced by GDM. The GDM also significantly decrease the level of DHA and n-3 PUFA in the fetal brain. GDM downregulated the Wnt3/β-catenin/MFSD2a signaling pathway which transfers n-3 PUFA in the placenta and fetal brain. The HF diet increased n-6 PUFAs in the maternal liver, correspondingly increasing linoleic acid (LA), gamma-linolenic acid (GLA), AA and total n-6 PUFA in the fetal brain, but decreased DHA in the fetal brain. However, HF diet only tended to decrease placental β-catenin and MFSD2a levels (P = 0.074, P = 0.098).
CONCLUSIONS: Maternal GDM could affect the fatty acid profile of the fetal brain both by downregulating the Wnt3/β-catenin/MFSD2a pathway of the placental-fetal barrier and by affecting maternal fatty acid metabolism.

Keywords:  DHA; Gestational diabetes mellitus; High-fat diet; MFSD2a; Polyunsaturated fatty acids

DOI:  https://doi.org/10.1016/j.tjnut.2023.12.045
Immunity. 2023 Dec 27. pii: S1074-7613(23)00533-2. [Epub ahead of print]

Trem2 expression in microglia is required to maintain normal neuronal bioenergetics during development.

Erica Tagliatti, Genni Desiato, Sara Mancinelli, Matteo Bizzotto, Maria C Gagliani, Elisa Faggiani, Rebeca Hernández-Soto, Andrea Cugurra, Paola Poliseno, Matteo Miotto, Rafael J Argüello, Fabia Filipello, Katia Cortese, Raffaella Morini, Simona Lodato, Michela Matteoli.

  Triggering receptor expressed on myeloid cells 2 (Trem2) is a myeloid cell-specific gene expressed in brain microglia, with variants that are associated with neurodegenerative diseases, including Alzheimer's disease. Trem2 is essential for microglia-mediated synaptic refinement, but whether Trem2 contributes to shaping neuronal development remains unclear. Here, we demonstrate that Trem2 plays a key role in controlling the bioenergetic profile of pyramidal neurons during development. In the absence of Trem2, developing neurons in the hippocampal cornus ammonis (CA)1 but not in CA3 subfield displayed compromised energetic metabolism, accompanied by reduced mitochondrial mass and abnormal organelle ultrastructure. This was paralleled by the transcriptional rearrangement of hippocampal pyramidal neurons at birth, with a pervasive alteration of metabolic, oxidative phosphorylation, and mitochondrial gene signatures, accompanied by a delay in the maturation of CA1 neurons. Our results unveil a role of Trem2 in controlling neuronal development by regulating the metabolic fitness of neurons in a region-specific manner.

Keywords:  TREM2; hippocampus; metabolism; microglia; mitochondria; neurodevelopment

DOI:  https://doi.org/10.1016/j.immuni.2023.12.002
Front Mol Neurosci. 2023 ;16 1323449

Severe central nervous system demyelination in Sanfilippo disease.

Mahsa Taherzadeh, Erjun Zhang, Irene Londono, Benjamin De Leener, Sophie Wang, Jonathan D Cooper, Timothy E Kennedy, Carlos R Morales, Zesheng Chen, Gregory A Lodygensky, Alexey V Pshezhetsky.

   Introduction: Chronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients.
Methods: Brain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms.
Results: Analyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or "zebra bodies" consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice.
Discussion: Our findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.

Keywords:  GM3 ganglioside; diffusion basis spectrum imaging; lysosomal storage; mucopolysaccharidosis; myelination; oligodendrocyte

DOI:  https://doi.org/10.3389/fnmol.2023.1323449
ACS Chem Neurosci. 2024 Jan 05.

Comparing Brain and Blood Lipidome Changes following Single and Repetitive Mild Traumatic Brain Injury in Rats.

Alexis N Pulliam, Eric C Gier, David A Gaul, Samuel G Moore, Facundo M Fernández, Michelle C LaPlaca.

  Traumatic brain injury (TBI) is a major health concern in the United States and globally, contributing to disability and long-term neurological problems. Lipid dysregulation after TBI is underexplored, and a better understanding of lipid turnover and degradation could point to novel biomarker candidates and therapeutic targets. Here, we investigated overlapping lipidome changes in the brain and blood using a data-driven discovery approach to understand lipid alterations in the brain and serum compartments acutely following mild TBI (mTBI) and the potential efflux of brain lipids to peripheral blood. The cortices and sera from male and female Sprague-Dawley rats were analyzed via ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) in both positive and negative ion modes following single and repetitive closed head impacts. The overlapping lipids in the data sets were identified with an in-house data dictionary for investigating lipid class changes. MS-based lipid profiling revealed overall increased changes in the serum compartment, while the brain lipids primarily showed decreased changes. Interestingly, there were prominent alterations in the sphingolipid class in the brain and blood compartments after single and repetitive injury, which may suggest efflux of brain sphingolipids into the blood after TBI. Genetic algorithms were used for predictive panel selection to classify injured and control samples with high sensitivity and specificity. These overlapping lipid panels primarily mapped to the glycerophospholipid metabolism pathway with Benjamini-Hochberg adjusted q-values less than 0.05. Collectively, these results detail overlapping lipidome changes following mTBI in the brain and blood compartments, increasing our understanding of TBI-related lipid dysregulation while identifying novel biomarker candidates.

Keywords:  Traumatic brain injury; blood biomarkers; brain biomarkers; lipidomics; ultra-high performance mass spectrometry

DOI:  https://doi.org/10.1021/acschemneuro.3c00603
bioRxiv. 2023 Dec 16. pii: 2023.12.15.571873. [Epub ahead of print]

SMPD4 mediated sphingolipid metabolism regulates brain and primary cilia development.

Katherine A Inskeep, Bryan Crase, Rolf W Stottmann.

Genetic variants in multiple sphingolipid biosynthesis genes cause human brain disorders. A recent study collected patients from twelve unrelated families with variants in the gene SMPD4 , a neutral sphingomyelinase which metabolizes sphingomyelin into ceramide at an early stage of the biosynthesis pathway. These patients have severe developmental brain malformations including microcephaly and cerebellar hypoplasia. However, the mechanism of SMPD4 was not known and we pursued a new mouse model. We hypothesized that the role of SMPD4 in producing ceramide is important for making primary cilia, a crucial organelle mediating cellular signaling. We found that the mouse model has cerebellar hypoplasia due to failure of Purkinje cell development. Human induced pluripotent stem cells exhibit neural progenitor cell death and have shortened primary cilia which is rescued by adding exogenous ceramide. SMPD4 production of ceramide is crucial for human brain development.

DOI: https://doi.org/10.1101/2023.12.15.571873
J Neurochem. 2024 Jan 05.

Over-expression of N-acetylaspartate synthase exacerbates pathological energetic deficit and accelerates cognitive decline in the 5xFAD mouse.

Jeremy S Francis, Quy Nguyen, Vladimir Markov, Paola Leone.

  N-acetylaspartate (NAA) is an abundant central nervous system amino acid derivative that is tightly coupled to mitochondria and energy metabolism in neurons. A reduced NAA signature is a prominent early pathological biomarker in multiple neurodegenerative diseases and becomes progressively more pronounced as disease advances. Because NAA synthesis requires aspartate drawn directly from mitochondria, we argued that this process is in direct competition with oxidative phosphorylation for substrate and that sustained high levels of NAA synthesis would be incompatible with pathological energy crisis. We show here that over-expression of the rate-limiting NAA synthetic enzyme in the hippocampus of the 5x familial Alzheimer's disease (5xFAD) mouse results in an exaggerated pathological ATP deficit and accelerated cognitive decline. Over-expression of NAA synthase did not increase amyloid burden or result in cell loss but did significantly deplete mitochondrial aspartate and impair the ability of mitochondria to oxidize glutamate for adenosine triphosphate (ATP) synthesis. These results define NAA as a sink for energetic substrate and suggest initial pathological reductions in NAA are part of a response to energetic crisis designed to preserve substrate bioavailability for mitochondrial ATP synthesis.

Keywords:  N-acetylaspartate; Neurodegenerative disease; metabolic decline

DOI:  https://doi.org/10.1111/jnc.16044
Biochim Biophys Acta Mol Cell Biol Lipids. 2024 Jan 03. pii: S1388-1981(23)00171-3. [Epub ahead of print] 159447

Discovery of novel diagnostic biomarkers for Sjögren-Larsson syndrome by untargeted lipidomics.

Frédéric M Vaz, Pippa Staps, Jan Bert van Klinken, Henk van Lenthe, Martin Vervaart, Ronald J A Wanders, Mia L Pras-Raves, Michel van Weeghel, Gajja S Salomons, Sacha Ferdinandusse, Ron A Wevers, Michèl A A P Willemsen.

   AIM: Sjögren-Larsson syndrome (SLS) is a rare neurometabolic disorder that mainly affects brain, eye and skin and is caused by deficiency of fatty aldehyde dehydrogenase. Our recent finding of a profoundly disturbed brain tissue lipidome in SLS prompted us to search for similar biomarkers in plasma as no functional test in blood is available for SLS.
METHODS AND RESULTS: We performed plasma lipidomics and used a newly developed bioinformatics tool to mine the untargeted part of the SLS plasma and brain lipidome to search for SLS biomarkers. Plasma lipidomics showed disturbed ether lipid metabolism in known lipid classes. Untargeted lipidomics of both plasma and brain (white and grey matter) uncovered two new endogenous lipid classes highly elevated in SLS. The first biomarker group were alkylphosphocholines/ethanolamines containing different lengths of alkyl-chains where some alkylphosphocholines were > 600-fold elevated in SLS plasma. The second group of biomarkers were a set of 5 features of unknown structure. Fragmentation studies suggested that they contain ubiquinol and phosphocholine and one feature was also found as a glucuronide conjugate in plasma. The plasma features were highly distinctive for SLS with levels >100-1000-fold the level in controls, if present at all. We speculate on the origin of the alkylphosphocholines/ethanolamines and the nature of the ubiquinol-containing metabolites.
CONCLUSIONS: The metabolites identified in this study represent novel endogenous lipid classes thus far unknown in humans. They represent the first plasma metabolite SLS-biomarkers and may also yield more insight into SLS pathophysiology.

Keywords:  ALDH3A2; Alkylphosphocholines; Alkylphosphoethanolamines; Farnesol metabolism; Pathophysiology; Plasma biomarkers; Ubiqinol-like molecules; Ubiquinol; Untargeted lipidomics pipeline

DOI:  https://doi.org/10.1016/j.bbalip.2023.159447
Glia. 2024 Jan 05.

Ascorbic acid and its transporter SVCT2, affect radial glia cells differentiation in postnatal stages.

Natalia Saldivia, Katterine Salazar, Manuel Cifuentes, Francisca Espinoza, Fiona E Harrison, Francisco Nualart.

  Radial glia (RG) cells generate neurons and glial cells that make up the cerebral cortex. Both in rodents and humans, these stem cells remain for a specific time after birth, named late radial glia (lRG). The knowledge of lRG and molecules that may be involved in their differentiation is based on very limited data. We analyzed whether ascorbic acid (AA) and its transporter SVCT2, are involved in lRG cells differentiation. We demonstrated that lRG cells are highly present between the first and fourth postnatal days. Anatomical characterization of lRG cells, revealed that lRG cells maintained their bipolar morphology and stem-like character. When lRG cells were labeled with adenovirus-eGFP at 1 postnatal day, we detected that some cells display an obvious migratory neuronal phenotype, suggesting that lRG cells continue generating neurons postnatally. Moreover, we demonstrated that SVCT2 was apically polarized in lRG cells. In vitro studies using the transgenic mice SVCT2+/- and SVCT2tg (SVCT2-overexpressing mouse), showed that decreased SVCT2 levels led to accelerated differentiation into astrocytes, whereas both AA treatment and elevated SVCT2 expression maintain the lRG cells in an undifferentiated state. In vivo overexpression of SVCT2 in lRG cells generated cells with a rounded morphology that were migratory and positive for proliferation and neuronal markers. We also examined mediators that can be involved in AA/SVCT2-modulated signaling pathways, determining that GSK3-β through AKT, mTORC2, and PDK1 is active in brains with high levels of SVCT2/AA. Our data provide new insights into the role of AA and SVCT2 in late RG cells.

Keywords:  SVCT2; ascorbic acid; cerebral cortex; late radial glia; neuronal differentiation; vitamin C

DOI:  https://doi.org/10.1002/glia.24498
bioRxiv. 2023 Dec 14. pii: 2023.12.13.571527. [Epub ahead of print]

Isolation and Lipidomic Profiling of Neuronal Lipid Droplets: Unveiling the Lipid Landscape for insights into Neurodegenerative Disorders.

Mukesh Kumar, Justin A Knapp, Kallol Gupta, Timothy A Ryan.

Recent advances have expanded the role of lipid droplets (LDs) beyond passive lipid storage, implicating their involvement in various metabolic processes across mammalian tissues. Neuronal LDs, long debated in existence, have been identified in several neural structures, raising questions about their contribution to neurodegenerative disorders. Elucidating the specific chemical makeup of these organelles within neurons is critical for understanding their implication in neural pathologies. This study outlines an improved methodology to stimulate and isolate mature LDs from cultured primary neurons, offering insights into their unique lipid-protein composition. Integrating this method with high-throughput techniques may unveil disease-specific alterations in lipid metabolism, providing avenues for potential therapeutic interventions.

DOI: https://doi.org/10.1101/2023.12.13.571527
EMBO J. 2024 Jan 02.

Structural insights into respiratory complex I deficiency and assembly from the mitochondrial disease-related ndufs4-/- mouse.

Zhan Yin, Ahmed-Noor A Agip, Hannah R Bridges, Judy Hirst.

  Respiratory complex I (NADH:ubiquinone oxidoreductase) is essential for cellular energy production and NAD+ homeostasis. Complex I mutations cause neuromuscular, mitochondrial diseases, such as Leigh Syndrome, but their molecular-level consequences remain poorly understood. Here, we use a popular complex I-linked mitochondrial disease model, the ndufs4-/- mouse, to define the structural, biochemical, and functional consequences of the absence of subunit NDUFS4. Cryo-EM analyses of the complex I from ndufs4-/- mouse hearts revealed a loose association of the NADH-dehydrogenase module, and discrete classes containing either assembly factor NDUFAF2 or subunit NDUFS6. Subunit NDUFA12, which replaces its paralogue NDUFAF2 in mature complex I, is absent from all classes, compounding the deletion of NDUFS4 and preventing maturation of an NDUFS4-free enzyme. We propose that NDUFAF2 recruits the NADH-dehydrogenase module during assembly of the complex. Taken together, the findings provide new molecular-level understanding of the ndufs4-/- mouse model and complex I-linked mitochondrial disease.

Keywords:  Complex I; Cryo-EM; Leigh Syndrome; Mitochondria; NADH:Ubiquinone Oxidoreductase

DOI:  https://doi.org/10.1038/s44318-023-00001-4
Curr Opin Clin Nutr Metab Care. 2024 Jan 04.

Modulation of beta-hydroxybutyrate in traumatic brain injury.

Niraj Arora, Dhaval Hitendrakumar Shastri, Utsav Prakashbhai Patel, Kunal Bhatia.

PURPOSE OF REVIEW: Traumatic brain injury (TBI) is a significant public health concern with substantial morbidity and mortality rates in the United States. Current management strategies primarily focus on symptomatic approaches and prevention of secondary complications. However, recent research highlights the potential role of ketone bodies, particularly beta-hydroxybutyrate (BHB), in modulating cellular processes involved in TBI. This article reviews the metabolism of BHB, its effect in TBI, and its potential therapeutic impact in TBI.
RECENT FINDINGS: BHB can be produced endogenously through fasting or administered exogenously through ketogenic diets, and oral or intravenous supplements. Studies suggest that BHB may offer several benefits in TBI, including reducing oxidative stress, inflammation, controlling excitotoxicity, promoting mitochondrial respiration, and supporting brain regeneration. Various strategies to modulate BHB levels are discussed, with exogenous ketone preparations emerging as a rapid and effective option.
SUMMARY: BHB offers potential therapeutic advantages in the comprehensive approach to improve outcomes for TBI patients. However, careful consideration of safety and efficacy is essential when incorporating it into TBI treatment protocols. The timing, dosage, and long-term effects of ketone use in TBI patients require further investigation to fully understand its potential benefits and limitations.

DOI: https://doi.org/10.1097/MCO.0000000000001008
Discov Ment Health. 2024 Jan 02. 4(1): 2

The neuropsychopharmacology of acetyl-L-carnitine (LAC): basic, translational and therapeutic implications.

Benedetta Bigio, Shofiul Azam, Aleksander A Mathé, Carla Nasca.

  Mitochondrial metabolism can contribute to nuclear histone acetylation among other epigenetic mechanisms. A central aspect of this signaling pathway is acetyl-L-carnitine (LAC), a pivotal mitochondrial metabolite best known for its role in fatty acid oxidation. Work from our and other groups suggested LAC as a novel epigenetic modulator of brain plasticity and a therapeutic target for clinical phenotypes of depression linked to childhood trauma. Aberrant mitochondrial metabolism of LAC has also been implicated in the pathophysiology of Alzheimer's disease. Furthermore, mitochondrial dysfunction is linked to other processes implicated in the pathophysiology of both major depressive disorders and Alzheimer's disease, such as oxidative stress, inflammation, and insulin resistance. In addition to the rapid epigenetic modulation of glutamatergic function, preclinical studies showed that boosting mitochondrial metabolism of LAC protects against oxidative stress, rapidly ameliorates insulin resistance, and reduces neuroinflammation by decreasing proinflammatory pathways such as NFkB in hippocampal and cortical neurons. These basic and translational neuroscience findings point to this mitochondrial signaling pathway as a potential target to identify novel mechanisms of brain plasticity and potential unique targets for therapeutic intervention targeted to specific clinical phenotypes.

Keywords:  Cognition; Depression; Glutamate; Hippocampus; Histone acetylation

DOI:  https://doi.org/10.1007/s44192-023-00056-z
Analyst. 2024 Jan 03.

Monitoring lipid alterations in Drosophila heads in an amyotrophic lateral sclerosis model with time-of-flight secondary ion mass spectrometry.

Minh Uyen Thi Le, Jeong Hyang Park, Jin Gyeong Son, Hyun Kyung Shon, Sunho Joh, Chang Geon Chung, Jae Ho Cho, Alexander Pirkl, Sung Bae Lee, Tae Geol Lee.

Lipid alterations in the brain are well-documented in disease and aging, but our understanding of their pathogenic implications remains incomplete. Recent technological advances in assessing lipid profiles have enabled us to intricately examine the spatiotemporal variations in lipid compositions within the complex brain characterized by diverse cell types and intricate neural networks. In this study, we coupled time-of-flight secondary ion mass spectrometry (ToF-SIMS) to an amyotrophic lateral sclerosis (ALS) Drosophila model, for the first time, to elucidate changes in the lipid landscape and investigate their potential role in the disease process, serving as a methodological and analytical complement to our prior approach that utilized matrix-assisted laser desorption/ionization mass spectrometry. The expansion of G4C2 repeats in the C9orf72 gene is the most prevalent genetic factor in ALS. Our findings indicate that expressing these repeats in fly brains elevates the levels of fatty acids, diacylglycerols, and ceramides during the early stages (day 5) of disease progression, preceding motor dysfunction. Using RNAi-based genetic screening targeting lipid regulators, we found that reducing fatty acid transport protein 1 (FATP1) and Acyl-CoA-binding protein (ACBP) alleviates the retinal degeneration caused by G4C2 repeat expression and also markedly restores the G4C2-dependent alterations in lipid profiles. Significantly, the expression of FATP1 and ACBP is upregulated in G4C2-expressing flies, suggesting their contribution to lipid dysregulation. Collectively, our novel use of ToF-SIMS with the ALS Drosophila model, alongside methodological and analytical improvements, successfully identifies crucial lipids and related genetic factors in ALS pathogenesis.

DOI: https://doi.org/10.1039/d3an01670f
Mol Pharmacol. 2023 Dec 15. pii: MOLPHARM-AR-2023-000788. [Epub ahead of print]

Expression of ceramide synthases in mice and their roles in regulating acyl-chain sphingolipids: A framework for baseline levels and future implications in aging and disease.

Whitney J Richardson, Sophia B Humphrey, Sophia M Sears, Nicholas A Hoffman, Andrew J Orwick, Mark A Doll, Chelsea L Doll, Catherine Xia, Maria Hernandez-Corbacho, Justin M Snider, Lina M Obeid, Yusuf A Hannun, Ashley J Snider, Leah J Siskind.

  Sphingolipids are an important class of lipids present in all eukaryotic cells that regulate critical cellular processes. Disturbances in sphingolipid homeostasis have been linked to several diseases in humans. Ceramides are central in sphingolipid metabolism and are largely synthesized by six ceramide synthase isoforms (CerS1-6), each with a preference for different fatty acyl chain lengths. While the tissue distribution of CerS mRNA expression in humans and the roles of CerS isoforms in synthesizing ceramides with different acyl chain lengths are known, it is unknown how CerS expression dictates ceramides and downstream metabolites within tissues. In this study, we analyzed sphingolipid levels and CerS mRNA expression in 3-month-old C57BL/6J mouse brain, heart, kidney, liver, lung, and skeletal muscle. The results showed that CerS expression and sphingolipid species abundance varied by tissue and that CerS expression was a predictor of ceramide species within tissues. Interestingly, though CerS expression was not predictive of complex sphingolipid species within all tissues, composite scores for CerSs contributions to total sphingolipids measured in each tissue correlated to CerS expression. Lastly, we determined that the most abundant ceramide species in mouse tissues aligned with CerS mRNA expression in corresponding human tissues (based on chain length preference), suggesting mice are relevant preclinical models for ceramide and sphingolipid research. Significance Statement The current study demonstrates that CerS expression in specific tissues correlates not only with ceramide species but contributes to the generation of complex sphingolipids as well. As many of the CerSs and/ or specific ceramide species have been implicated in disease, these studies suggest the potential for CerSs as therapeutic targets and the use of sphingolipid species as diagnostics in specific tissues.

Keywords:  Ceramide; lipids; sphingolipids

DOI:  https://doi.org/10.1124/molpharm.123.000788
Arch Pediatr. 2024 Jan;pii: S0929-693X(23)00179-3. [Epub ahead of print]31(1): 85-88

Low C0 and normal C16 and C18:1 masking the diagnosis of carnitine palmitoyltransferase II deficiency including a novel CPT2 variant: A case report.

Shuting Wang, Chengming Diao, Junhong Leng.

  The cases were a pair of siblings with a carnitine palmitoyltransferase (CPT2) deficiency detected by tandem mass spectrometry. Their C16 and C18:1 levels were both within the normal range, while C0 was low, and the (C16+C18:1)/C2 ratio was high. Following genetic testing, a novel CPT2 gene mutation was identified in both patients. The male patient had a normal growth rate during 5 years of follow-up after treatment. By contrast, the female patient did not take l-carnitine supplements and died after an infectious disease-associated illness when she was 1 year old. These data emphasize the need to raise awareness about CPT2 deficiency so as to correctly diagnose and accurately manage the disease.

Keywords:  Carnitine palmitoyltransferase 2 (CPT2) deficiency; Inherited metabolic disease (IMD); Mitochondrial long-chain fatty acid oxidation; Tandem mass spectrometry (TMS)

DOI:  https://doi.org/10.1016/j.arcped.2023.09.010