bims-medebr 2024-07-14 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2024–07–14
thirty-one papers selected by
Regina F. Fernández, Johns Hopkins University

The effects of APOE4 and familial Alzheimer's disease mutations on free fatty acid profiles in mouse brain are age- and sex-dependent.
Long-term use of investigational β-Hydroxybutyrate salts in children with multiple acyl-CoA dehydrogenase or pyruvate dehydrogenase deficiency.
Omega-3 blood biomarkers relate to brain glucose uptake in individuals at risk of Alzheimer's disease dementia.
Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.
Cholesterol metabolism: physiological versus pathological aspects in intracerebral hemorrhage.
Roles for PMP22 in Schwann cell cholesterol homeostasis in health and disease.
Lipids shape brain function through ion channel and receptor modulations: physiological mechanisms and clinical perspectives.
Quantifying ABCA1/apoA-1 Signaling Pathways with AFM Imaging and Lipidomic Analysis.
Aging AdipoR2-deficient mice are hyperactive with enlarged brains excessively rich in saturated fatty acids.
DHA dietary intervention caused different hippocampal lipid and protein profile in ApoE-/- and C57BL/6J mice.
An efficient and high-throughput method for the evaluation of mitochondrial dysfunction in frozen brain samples after traumatic brain injury.
Disruption of mitochondrial pyruvate oxidation in dorsal root ganglia drives persistent nociceptive sensitization and causes pervasive transcriptomic alterations.
Association between Visceral Adipose Tissue Metabolism and Cerebral Glucose Metabolism in Patients with Cognitive Impairment.
Medium-chain triglycerides combined with DHA improve cognitive function by inhibiting neurocyte apoptosis of the brain in SAMP8 mice.
Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease.
Dietary Supplementation with n-3 Polyunsaturated Fatty Acids Delays the Phenotypic Manifestation of Krabbe Disease and Partially Restores Lipid Mediator Production in the Brain-Study in a Mouse Model of the Disease.
Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances.
A Facile LC-MS Method for Profiling Cholesterol and Cholesteryl Esters in Mammalian Cells and Tissues.
Diacylglycerol Signaling in Retinal Ganglion Cells.
Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses.
Using lipid binding proteins and advanced microscopy to study lipid domains.
Visualization of Phospholipid Synthesis on Tissue Sections Using Functional Mass Spectrometry Imaging.
Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.
Short-chain fatty acids suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in experimental autoimmune encephalomyelitis mice.
Analysis of Sphingosine and Sphinganine from the Aqueous Humor for Signaling Studies Using Ultrahigh-Performance Liquid Chromatography-Mass Spectrometry.
Galactokinase 1 is the source of elevated galactose-1-phosphate and cerebrosides are modestly reduced in a mouse model of classic galactosemia.
Cell type-specific and subcellular expression of phospholipid phosphatase-related proteins to modulate lyso-phosphatidic acid synaptic signaling in the developing and adult CNS.
Luteolin Mitigates D-Galactose-Induced Brain Ageing in Rats: SIRT1-Mediated Neuroprotection.
Purinosomes and Purine Metabolism in Mammalian Neural Development: A Review.
27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior.
Citrin deficiency-The East-side story.

J Neurochem. 2024 Jul 13.

The effects of APOE4 and familial Alzheimer's disease mutations on free fatty acid profiles in mouse brain are age- and sex-dependent.

Sandra den Hoedt, Simone M Crivelli, Kristien Y Dorst-Lagerwerf, Frank P J Leijten, Mario Losen, Helga E de Vries, Eric J G Sijbrands, Adrie J M Verhoeven, Pilar Martinez-Martinez, Monique T Mulder.

  APOE4 encoding apolipoprotein (Apo)E4 is the strongest genetic risk factor for Alzheimer's disease (AD). ApoE is key in intercellular lipid trafficking. Fatty acids are essential for brain integrity and cognitive performance and are implicated in neurodegeneration. We determined the sex- and age-dependent effect of AD and APOE4 on brain free fatty acid (FFA) profiles. FFA profiles were determined by LC-MS/MS in hippocampus, cortex, and cerebellum of female and male, young (≤3 months) and older (>5 months), transgenic APOE3 and APOE4 mice with and without five familial AD (FAD) mutations (16 groups; n = 7-10 each). In the different brain regions, females had higher levels than males of either saturated or polyunsaturated FFAs or both. In the hippocampus of young males, but not of older males, APOE4 and FAD each induced 1.3-fold higher levels of almost all FFAs. In young and older females, FAD and to a less extent APOE4-induced shifts among saturated, monounsaturated, and polyunsaturated FFAs without affecting total FFA levels. In cortex and cerebellum, APOE4 and FAD had only minor effects on individual FFAs. The effects of APOE4 and FAD on FFA levels and FFA profiles in the three brain regions were strongly dependent of sex and age, particularly in the hippocampus. Here, most FFAs that are affected by FAD are similarly affected by APOE4. Since APOE4 and FAD affected hippocampal FFA profiles already at young age, these APOE4-induced alterations may modulate the pathogenesis of AD.

Keywords:  Alzheimer's disease; apolipoprotein E4; free fatty acids; neurodegeneration

DOI:  https://doi.org/10.1111/jnc.16176
Mol Genet Metab Rep. 2024 Sep;40 101104

Long-term use of investigational β-Hydroxybutyrate salts in children with multiple acyl-CoA dehydrogenase or pyruvate dehydrogenase deficiency.

Andrew A M Morris, Bernard Cuenoud, Philippe Delerive, Helen Mundy, Bernd C Schwahn.

  Several disorders of energy metabolism have been treated with exogenous ketone bodies. The benefit of this treatment is best documented in multiple acyl-CoA dehydrogenase deficiency (MADD) (MIM#231680). One might also expect ketone bodies to help in other disorders with impaired ketogenesis or in conditions that profit from a ketogenic diet. Here, we report the use of a novel preparation of dextro-β-hydroxybutyrate (D-βHB) salts in two cases of MADD and one case of pyruvate dehydrogenase (PDH) deficiency (MIM#312170). The two patients with MADD had previously been on a racemic mixture of D- and L‑sodium hydroxybutyrate. Patient #1 found D-βHB more palatable, and the change in formulation corrected hypernatraemia in patient #2. The patient with PDH deficiency was on a ketogenic diet but had not previously been given hydroxybutyrate. In this case, the addition of D-βHB improved ketosis. We conclude that NHS101 is a good candidate for further clinical studies in this group of diseases of inborn errors of metabolism.

Keywords:  Glutaric aciduria II; Ketone bodies; MADD; Pyruvate dehydrogenase deficiency; β-Hydroxybutyrate

DOI:  https://doi.org/10.1016/j.ymgmr.2024.101104
Alzheimers Dement (Amst). 2024 Jul-Sep;16(3):16(3): e12596

Omega-3 blood biomarkers relate to brain glucose uptake in individuals at risk of Alzheimer's disease dementia.

ALFA study

   INTRODUCTION: Brain glucose hypometabolism is a preclinical feature of Alzheimer's disease (AD). Dietary omega-3 fatty acids promote brain glucose metabolism, but clinical research is incipient. Circulating omega-3s objectively reflect their dietary intake.
METHODS: This was a cross-sectional study in 320 cognitively unimpaired participants at increased risk of AD dementia. Using lipidomics, we determined blood docosahexaenoic (DHA) and alpha-linolenic (ALA) acid levels (omega-3s from marine and plant origin, respectively). We assessed brain glucose metabolism using [18-F]-fluorodeoxyglucose (FDG) positron emission tomography (PET).
RESULTS: Blood ALA directly related to FDG uptake in brain areas known to be affected in AD. Stronger associations were observed in apolipoprotein E ε4 carriers and homozygotes. For DHA, significant direct associations were restricted to amyloid beta-positive tau-positive participants.
DISCUSSION: Blood omega-3 directly relate to preserved glucose metabolism in AD-vulnerable brain regions in individuals at increased risk of AD dementia. This adds to the benefits of omega-3 supplementation in the preclinical stage of AD dementia.
Highlights: Blood omega-3s were related to brain glucose uptake in participants at risk of Alzheimer's disease (AD) dementia.Complementary associations were observed for omega-3 from marine and plant sources.Foods rich in omega-3 might be useful in early features of AD.

Keywords:  biomarkers; diet; fatty fish; fish oil; nuts; n‐3 fatty acids; polyunsaturated fatty acids; walnuts

DOI:  https://doi.org/10.1002/dad2.12596
bioRxiv. 2024 Jun 28. pii: 2024.06.23.598940. [Epub ahead of print]

Restoring hippocampal glucose metabolism rescues cognition across Alzheimer's disease pathologies.

Paras S Minhas, Jeffrey R Jones, Amira Latif-Hernandez, Yuki Sugiura, Aarooran S Durairaj, Takeshi Uenaka, Qian Wang, Siddhita D Mhatre, Ling Liu, Travis Conley, Hannah Ennerfelt, Yoo Jin Jung, Praveena Prasad, Brenita C Jenkins, Ryan Goodman, Traci Newmeyer, Kelly Heard, Austin Kang, Edward N Wilson, Erik M Ullian, Geidy E Serrano, Thomas G Beach, Joshua D Rabinowitz, Marius Wernig, Makoto Suematsu, Frank M Longo, Melanie R McReynolds, Fred H Gage, Katrin I Andreasson.

Impaired cerebral glucose metabolism is a pathologic feature of Alzheimer Disease (AD), and recent proteomic studies highlight a disruption of glial carbohydrate metabolism with disease progression. Here, we report that inhibition of indoleamine-2,3-dioxygenase 1 (IDO1), which metabolizes tryptophan to kynurenine (KYN) in the first step of the kynurenine pathway, rescues hippocampal memory function and plasticity in preclinical models of amyloid and tau pathology by restoring astrocytic metabolic support of neurons. Activation of IDO1 in astrocytes by amyloid-beta 42 and tau oligomers, two major pathological effectors in AD, increases KYN and suppresses glycolysis in an AhR-dependent manner. Conversely, pharmacological IDO1 inhibition restores glycolysis and lactate production. In amyloid-producing APP Swe -PS1 ΔE9 and 5XFAD mice and in tau-producing P301S mice, IDO1 inhibition restores spatial memory and improves hippocampal glucose metabolism by metabolomic and MALDI-MS analyses. IDO1 blockade also rescues hippocampal long-term potentiation (LTP) in a monocarboxylate transporter (MCT)-dependent manner, suggesting that IDO1 activity disrupts astrocytic metabolic support of neurons. Indeed, in vitro mass-labeling of human astrocytes demonstrates that IDO1 regulates astrocyte generation of lactate that is then taken up by human neurons. In co-cultures of astrocytes and neurons derived from AD subjects, deficient astrocyte lactate transfer to neurons was corrected by IDO1 inhibition, resulting in improved neuronal glucose metabolism. Thus, IDO1 activity disrupts astrocytic metabolic support of neurons across both amyloid and tau pathologies and in a model of AD iPSC-derived neurons. These findings also suggest that IDO1 inhibitors developed for adjunctive therapy in cancer could be repurposed for treatment of amyloid- and tau-mediated neurodegenerative diseases.

DOI: https://doi.org/10.1101/2024.06.23.598940
Neural Regen Res. 2025 Apr 01. 20(4): 1015-1030

Cholesterol metabolism: physiological versus pathological aspects in intracerebral hemorrhage.

Ruoyu Huang, Qiuyu Pang, Lexin Zheng, Jiaxi Lin, Hanxi Li, Lingbo Wan, Tao Wang.

Cholesterol is an important component of plasma membranes and participates in many basic life functions, such as the maintenance of cell membrane stability, the synthesis of steroid hormones, and myelination. Cholesterol plays a key role in the establishment and maintenance of the central nervous system. The brain contains 20% of the whole body's cholesterol, 80% of which is located within myelin. A huge number of processes (e.g., the sterol regulatory element-binding protein pathway and liver X receptor pathway) participate in the regulation of cholesterol metabolism in the brain via mechanisms that include cholesterol biosynthesis, intracellular transport, and efflux. Certain brain injuries or diseases involving crosstalk among the processes above can affect normal cholesterol metabolism to induce detrimental consequences. Therefore, we hypothesized that cholesterol-related molecules and pathways can serve as therapeutic targets for central nervous system diseases. Intracerebral hemorrhage is the most severe hemorrhagic stroke subtype, with high mortality and morbidity. Historical cholesterol levels are associated with the risk of intracerebral hemorrhage. Moreover, secondary pathological changes after intracerebral hemorrhage are associated with cholesterol metabolism dysregulation, such as neuroinflammation, demyelination, and multiple types of programmed cell death. Intracellular cholesterol accumulation in the brain has been found after intracerebral hemorrhage. In this paper, we review normal cholesterol metabolism in the central nervous system, the mechanisms known to participate in the disturbance of cholesterol metabolism after intracerebral hemorrhage, and the links between cholesterol metabolism and cell death. We also review several possible and constructive therapeutic targets identified based on cholesterol metabolism to provide cholesterol-based perspectives and a reference for those interested in the treatment of intracerebral hemorrhage.

DOI: https://doi.org/10.4103/NRR.NRR-D-23-01462
Biochem Soc Trans. 2024 Jul 09. pii: BST20231359. [Epub ahead of print]

Roles for PMP22 in Schwann cell cholesterol homeostasis in health and disease.

Katherine M Stefanski, Mason C Wilkinson, Charles R Sanders.

  Underexpression, overexpression, and point mutations in peripheral myelin protein 22 (PMP22) cause most cases of Charcot-Marie-Tooth disease (CMTD). While its exact functions remain unclear, PMP22 is clearly essential for formation and maintenance of healthy myelin in the peripheral nervous system. This review explores emerging evidence for roles of PMP22 in cholesterol homeostasis. First, we highlight dysregulation of lipid metabolism in PMP22-based forms of CMTD and recently-discovered interactions between PMP22 and cholesterol biosynthesis machinery. We then examine data that demonstrates PMP22 and cholesterol co-traffic in cells and co-localize in lipid rafts, including how disease-causing PMP22 mutations result in aberrations in cholesterol localization. Finally, we examine roles for interactions between PMP22 and ABCA1 in cholesterol efflux. Together, this emerging body of evidence suggests that PMP22 plays a role in facilitating enhanced cholesterol synthesis and trafficking necessary for production and maintenance of healthy myelin.

Keywords:  Charcot-Marie-Tooth disease; PMP22; cholesterol; myelin; peripheral myelin protein 22; peripheral nervous system

DOI:  https://doi.org/10.1042/BST20231359
Physiol Rev. 2024 Jul 11.

Lipids shape brain function through ion channel and receptor modulations: physiological mechanisms and clinical perspectives.

Salvatore Incontro, Maria Laura Musella, Malika Sammari, Coralie Di Scala, Jacques Fantini, Dominique Debanne.

  Lipids represent the most abundant molecular type in the brain with a fat content of approximately 60% of the dry brain weight in humans. Despite this fact, little attention has been paid to circumscribe the dynamic role of lipids in brain function and disease. Membrane lipids such as cholesterol, phosphoinositide, sphingolipids, arachidonic acid and endocannabinoids finely regulate both synaptic receptors and ion channels that insure critical neural functions. After a brief introduction on brain lipids and their respective properties, we review here their role in regulating synaptic function and ion channel activity, action potential propagation, neuronal development, functional plasticity and their contribution in the development of neurological and neuropsychiatric diseases. We also provide possible directions for future research on lipid function in brain plasticity and diseases.

Keywords:  cholesterol; endocannabinoids; ion channel; neuron; synapse

DOI:  https://doi.org/10.1152/physrev.00004.2024
Methods Mol Biol. 2024 ;2816 205-222

Quantifying ABCA1/apoA-1 Signaling Pathways with AFM Imaging and Lipidomic Analysis.

Carolina Cruz-Wegener, Jonah Kutell, Louay Aldaher, Noa deHaseth, Sanjoy K Bhattacharya, Noel Ziebarth.

  The role of lipid metabolic pathways in the pathophysiology of primary open-angle glaucoma (POAG) has been thoroughly elucidated, with pathways involved in lipid-related disorders such as hypercholesterolemia and hyperlipoprotein accumulation being of particular interest. The ABCA1/apoA-1 transduction pathway moderates reverse cholesterol transport (RCT), facilitating the transport of free cholesterol (FC) and phospholipids (PL) and preventing intracellular lipid aggregates in retinal ganglion cells (RGCs) due to excess FCs and PLs. A deficiency of ABCA1 transporters, and thus, dysregulation of the ABCA1/apoA-1 transduction pathway, may potentiate cellular lipid accumulation, which affects the structural and mechanical features of the cholesterol-rich RGC membranes. Atomic force microscopy (AFM) is a cutting-edge imaging technique suitable for imaging topographical surfaces of a biological specimen and determining its mechanical properties and structural features. The versatility and precision of this technique may prove beneficial in understanding the effects of ABCA1/apoA-1 pathway downregulation and decreased cholesterol efflux in RGCs and their membranes. In this protocol, ABCA1-/- RGC mouse models are prepared over the course of 3 days and are then compared with non-knockout ABCA1 RGC mouse models through AFM imaging of topographical surfaces to examine the difference in membrane dynamics of knockout vs. non-knockout models. Intracellular and extracellular levels of lipids are quantified through high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS).

Keywords:  ABCA1; Atomic force microscopy; Cholesterol efflux; Lipid signaling; Lipidomics; Mass spectrometry; Retinal ganglion cells; Tapping mode; apoA-1

DOI:  https://doi.org/10.1007/978-1-0716-3902-3_19
FASEB J. 2024 Jul 31. 38(14): e23815

Aging AdipoR2-deficient mice are hyperactive with enlarged brains excessively rich in saturated fatty acids.

Mario Ruiz, Ranjan Devkota, Per-Olof Bergh, Ali Moussavi Nik, Sebastian Blid Sköldheden, Jorge Mondejar-Duran, Maximilian Tufvesson-Alm, Mohammad Bohlooly-Y, Diego Sanchez, Peter Carlsson, Marcus Henricsson, Elisabet Jerlhag, Jan Borén, Marc Pilon.

  To investigate how the fatty acid composition of brain phospholipids influences brain-specific processes, we leveraged the AdipoR2 (adiponectin receptor 2) knockout mouse model in which the brain is enlarged, and cellular membranes are excessively rich in saturated fatty acids. Lipidomics analysis of brains at 2, 7, and 18 months of age showed that phosphatidylcholines, which make up about two-thirds of all cerebrum membrane lipids, contain a gross excess of saturated fatty acids in AdipoR2 knockout mice, and that this is mostly attributed to an excess palmitic acid (C16:0) at the expense of oleic acid (C18:1), consistent with a defect in fatty acid desaturation and elongation in the mutant. Specifically, there was a ~12% increase in the overall saturated fatty acid content within phosphatidylcholines and a ~30% increase in phosphatidylcholines containing two palmitic acids. Phosphatidylethanolamines, sphingomyelins, ceramides, lactosylceramides, and dihydroceramides also showed an excess of saturated fatty acids in the AdipoR2 knockout mice while nervonic acid (C24:1) was enriched at the expense of shorter saturated fatty acids in glyceroceramides. Similar defects were found in the cerebellum and myelin sheaths. Histology showed that cell density is lower in the cerebrum of AdipoR2 knockout mice, but electron microscopy did not detect reproducible defects in the ultrastructure of cerebrum neurons, though proteomics analysis showed an enrichment of electron transport chain proteins in the cerebellum. Behavioral tests showed that older (33 weeks old) AdipoR2 knockout mice are hyperactive and anxious compared to control mice of a similar age. Also, in contrast to control mice, the AdipoR2 knockout mice do not gain weight in old age but do have normal lifespans. We conclude that an excess fatty acid saturation in brain phospholipids is accompanied by hyperactivity but seems otherwise well tolerated.

Keywords:  adiponectin receptor; anxiety; brain; cell membrane; fatty acids; phospholipids

DOI:  https://doi.org/10.1096/fj.202400293RR
Biomed Pharmacother. 2024 Jul 05. pii: S0753-3322(24)00972-7. [Epub ahead of print]177 117088

DHA dietary intervention caused different hippocampal lipid and protein profile in ApoE-/- and C57BL/6J mice.

Lu Liu, Jingjing Xu, Xiaochen Huang, Ying Wang, Xiaojun Ma, Xixiang Wang, Yu Liu, Xiuwen Ren, Jiahao Li, Yueyong Wang, Shaobo Zhou, Linhong Yuan.

   BACKGROUND: Changes in protein and lipid levels may occur in the Alzheimer's disease brain, and DHA can have beneficial effects on it. To investigate the impact of DHA dietary intervention on brain protein and lipid profile in ApoE-/- mice and C57 mice.
METHOD: Three-month-old ApoE-/- mice and C57 mice were randomly divided into two groups respectively, and fed with control diet and DHA-fortified diet for five months. Cortical TC, HDL-C and LDL-C levels and cholesterol metabolism-related protein expression were measured by ELISA or immunohistochemistry methods. Hippocampus were collected for proteomic and lipidomics analysis by LC-MS/MS and differential proteins and lipid metabolites were screened and further analyzed by GO functional annotation and KEGG pathway enrichment analysis.
RESULTS: DHA intervention decreased cortical TC level in both C57 and ApoE-/- mice (P < 0.05), but caused different change of cortical HDL-C, LDL-C level and LDL-C/HDL-C ratio in C57 and ApoE-/- mice (P < 0.05). Discrepant cortical and hippocampal LDLR, ABCG1, Lox1 and SORT1 protein expression was found between C57 and ApoE-/- mice (P < 0.05), and DHA treatment caused different changes of these proteins in C57 and ApoE-/- mice (P < 0.05). Differential hippocampal proteins and lipids profile were found in C57 and ApoE-/- mice before and after DHA treatment, which were mainly involved in vesicular transport and phospholipid metabolic pathways.
CONCLUSION: ApoE genetic defect caused abnormal cholesterol metabolism, and affected protein and lipid profile, as well as discrepant response of hippocampal protein and lipids profile in the brain of mice given DHA fortified diet intervention.

Keywords:  ApoE-/- mice; DHA; Dietary intervention, proteomics; Lipidomics

DOI:  https://doi.org/10.1016/j.biopha.2024.117088
Front Mol Biosci. 2024 ;11 1378536

An efficient and high-throughput method for the evaluation of mitochondrial dysfunction in frozen brain samples after traumatic brain injury.

Hemendra J Vekaria, Olivia J Kalimon, Paresh Prajapati, Gopal V Velmurugan, Patrick G Sullivan.

  Mitochondrial function analysis is a well-established method used in preclinical and clinical investigations to assess pathophysiological changes in various disease states, including traumatic brain injury (TBI). Although there are multiple approaches to assess mitochondrial function, one common method involves respirometric assays utilizing either Clark-type oxygen electrodes or fluorescent-based Seahorse analysis (Agilent). However, these functional analysis methods are typically limited to the availability of freshly isolated tissue samples due to the compromise of the electron transport chain (ETC) upon storage, caused by freeze-thaw-mediated breakdown of mitochondrial membranes. In this study, we propose and refine a method for evaluating electron flux through the ETC, encompassing complexes I, II, and IV, in frozen homogenates or mitochondrial samples within a single well of a Seahorse plate. Initially, we demonstrate the impact of TBI on freshly isolated mitochondria using the conventional oxidative phosphorylation protocol (OxPP), followed by a comparison with ETC analysis conducted on frozen tissue samples within the context of a controlled cortical impact (CCI) model of TBI. Additionally, we explore the effects of mitochondrial isolation from fresh versus snap-frozen brain tissues and their storage at -80°C, assessing its impact on electron transport chain protocol (ETCP) activity. Our findings indicate that while both sets of samples were frozen at a single time point, mitochondria from snap-frozen tissues exhibited reduced injury effects compared to preparations from fresh tissues, which were either homogenized or isolated into mitochondria and subsequently frozen for later use. Thus, we demonstrate that the preparation of homogenates or isolated mitochondria can serve as an appropriate method for storing brain samples, allowing for later analysis of mitochondrial function, following TBI using ETCP.

Keywords:  OxPhos; Seahorse assay; electron transport chain; frozen tissue; mitochondria; respiration; traumatic brain injury

DOI:  https://doi.org/10.3389/fmolb.2024.1378536
Pain. 2024 Jul 01. 165(7): 1531-1549

Disruption of mitochondrial pyruvate oxidation in dorsal root ganglia drives persistent nociceptive sensitization and causes pervasive transcriptomic alterations.

Md Mamunul Haque, Panjamurthy Kuppusamy, Ohannes K Melemedjian.

ABSTRACT: Metabolism is inextricably linked to every aspect of cellular function. In addition to energy production and biosynthesis, metabolism plays a crucial role in regulating signal transduction and gene expression. Altered metabolic states have been shown to maintain aberrant signaling and transcription, contributing to diseases like cancer, cardiovascular disease, and neurodegeneration. Metabolic gene polymorphisms and defects are also associated with chronic pain conditions, as are increased levels of nerve growth factor (NGF). However, the mechanisms by which NGF may modulate sensory neuron metabolism remain unclear. This study demonstrated that intraplantar NGF injection reprograms sensory neuron metabolism. Nerve growth factor suppressed mitochondrial pyruvate oxidation and enhanced lactate extrusion, requiring 24 hours to increase lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 (PDHK1) expression. Inhibiting these metabolic enzymes reversed NGF-mediated effects. Remarkably, directly disrupting mitochondrial pyruvate oxidation induced severe, persistent allodynia, implicating this metabolic dysfunction in chronic pain. Nanopore long-read sequencing of poly(A) mRNA uncovered extensive transcriptomic changes upon metabolic disruption, including altered gene expression, splicing, and poly(A) tail lengths. By linking metabolic disturbance of dorsal root ganglia to transcriptome reprogramming, this study enhances our understanding of the mechanisms underlying persistent nociceptive sensitization. These findings imply that impaired mitochondrial pyruvate oxidation may drive chronic pain, possibly by impacting transcriptomic regulation. Exploring these metabolite-driven mechanisms further might reveal novel therapeutic targets for intractable pain.

DOI: https://doi.org/10.1097/j.pain.0000000000003158
Int J Mol Sci. 2024 Jul 08. pii: 7479. [Epub ahead of print]25(13):

Association between Visceral Adipose Tissue Metabolism and Cerebral Glucose Metabolism in Patients with Cognitive Impairment.

Mi-Hee Yu, Ji Sun Lim, Hyon-Ah Yi, Kyoung Sook Won, Hae Won Kim.

  Visceral adipose tissue (VAT) dysfunction has been recently recognized as a potential contributor to the development of Alzheimer's disease (AD). This study aimed to explore the relationship between VAT metabolism and cerebral glucose metabolism in patients with cognitive impairment. This cross-sectional prospective study included 54 patients who underwent 18F-fluorodeoxyglucose (18F-FDG) brain and torso positron emission tomography/computed tomography (PET/CT), and neuropsychological evaluations. VAT metabolism was measured by 18F-FDG torso PET/CT, and cerebral glucose metabolism was measured using 18F-FDG brain PET/CT. A voxel-based analysis revealed that the high-VAT-metabolism group exhibited a significantly lower cerebral glucose metabolism in AD-signature regions such as the parietal and temporal cortices. In the volume-of-interest analysis, multiple linear regression analyses with adjustment for age, sex, and white matter hyperintensity volume revealed that VAT metabolism was negatively associated with cerebral glucose metabolism in AD-signature regions. In addition, higher VAT metabolism was correlated with poorer outcomes on cognitive assessments, including the Korean Boston Naming Test, Rey Complex Figure Test immediate recall, and the Controlled Oral Word Association Test. In conclusion, our study revealed significant relationships among VAT metabolism, cerebral glucose metabolism, and cognitive function. This suggests that VAT dysfunction actively contributes to the neurodegenerative processes characteristic of AD, making VAT dysfunction targeting a novel AD therapy approach.

Keywords:  Alzheimer’s disease; cerebral glucose metabolism; cognitive impairment; visceral adipose tissue metabolism

DOI:  https://doi.org/10.3390/ijms25137479
Exp Gerontol. 2024 Jul 09. pii: S0531-5565(24)00162-1. [Epub ahead of print] 112520

Medium-chain triglycerides combined with DHA improve cognitive function by inhibiting neurocyte apoptosis of the brain in SAMP8 mice.

Yue Sun, Dezheng Zhou, Yue Wang, Zehao Wang, Dalong Zhang, Zhiyong Qian, Jing Yan, Zhenshu Li, Guowei Huang, Wen Li.

  Medium-chain triglycerides (MCTs) and docosahexaenoic acid (DHA, Cn-3, 22:6) are essential in improving cognitive function and protecting neurocytes. This study explored the effects of the combined intervention of MCTs and DHA on inhibiting neurocyte apoptosis of the brain and improving cognitive function in senescence-accelerated mouse-prone 8 (SAMP8). Four-month-old male SAMP8 mice were randomly divided into four treatment groups (12 mice/group): DHA, MCT, DHA + MCT, and control groups, which intervened for seven months. Twelve age-matched male senescence-accelerated mouse resistant 1 (SAMR1) was used as the natural aging group. TUNEL assay and HE staining were used to assess neurocyte apoptosis and damage in the brain of mice. Moreover, the cognitive function was analyzed using the Morris water maze (MWM) and open field (OF) tests. The results showed that the cognitive function of 11-month-old SAMP8 mice decreased with age, and further pathological examination revealed the damaged neurocyte structure, karyopyknosis, cell atrophy, and even apoptosis. MCTs combined with DHA supplementation could increase octanoic acid (C8:0), decanoic acid (C10:0), and DHA levels in the serum, inhibit neurocyte apoptosis, improve neurocyte damage, moreover delay age-related cognitive decline after seven-month treatment. Furthermore, combining MCTs and DHA was significantly more beneficial than MCTs or DHA alone. In conclusion, MCTs combined with DHA could delay cognitive decline by inhibiting neurocyte apoptosis of the brain in SAMP8 mice.

Keywords:  Apoptosis; Cognitive function; Docosahexaenoic acid; Medium-chain triglycerides; Mouse; Neurocyte

DOI:  https://doi.org/10.1016/j.exger.2024.112520
Immunol Rev. 2024 Jul 11.

Ketone body metabolism and the NLRP3 inflammasome in Alzheimer's disease.

Daniel C Shippy, Abigail H Evered, Tyler K Ulland.

  Alzheimer's disease (AD) is a degenerative brain disorder and the most common form of dementia. AD pathology is characterized by senile plaques and neurofibrillary tangles (NFTs) composed of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Neuroinflammation has been shown to drive Aβ and tau pathology, with evidence suggesting the nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome as a key pathway in AD pathogenesis. NLRP3 inflammasome activation in microglia, the primary immune effector cells of the brain, results in caspase-1 activation and secretion of IL-1β and IL-18. Recent studies have demonstrated a dramatic interplay between the metabolic state and effector functions of immune cells. Microglial metabolism in AD is of particular interest, as ketone bodies (acetone, acetoacetate (AcAc), and β-hydroxybutyrate (BHB)) serve as an alternative energy source when glucose utilization is compromised in the brain of patients with AD. Furthermore, reduced cerebral glucose metabolism concomitant with increased BHB levels has been demonstrated to inhibit NLRP3 inflammasome activation. Here, we review the role of the NLRP3 inflammasome and microglial ketone body metabolism in AD pathogenesis. We also highlight NLRP3 inflammasome inhibition by several ketone body therapies as a promising new treatment strategy for AD.

Keywords:  Alzheimer's disease; Beta‐hydroxybutyrate; NLRP3 inflammasome; ketone bodies; metabolism; microglia

DOI:  https://doi.org/10.1111/imr.13365
Int J Mol Sci. 2024 Jun 28. pii: 7149. [Epub ahead of print]25(13):

Dietary Supplementation with n-3 Polyunsaturated Fatty Acids Delays the Phenotypic Manifestation of Krabbe Disease and Partially Restores Lipid Mediator Production in the Brain-Study in a Mouse Model of the Disease.

Cinzia Signorini, Giovanna Pannuzzo, Adriana Carol Eleonora Graziano, Elena Moretti, Giulia Collodel, Venera Cardile.

  Lipid mediators from fatty acid oxidation have been shown to be associated with the severity of Krabbe disease (KD), a disorder linked to mutations in the galactosylceramidase (GALC) gene. This study aims to investigate the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on KD traits and fatty acid metabolism using Twitcher (Tw) animals as a natural model for KD. Wild-type (Wt), heterozygous (Ht), and affected Tw animals were treated orally with 36 mg n-3 PUFAs/kg body weight/day from 10 to 35 days of life. The end product of PUFA peroxidation (8-isoprostane), the lipid mediator involved in the resolution of inflammatory exudates (resolvin D1), and the total amount of n-3 PUFAs were analyzed in the brains of mice. In Tw mice, supplementation with n-3 PUFAs delayed the manifestation of disease symptoms (p < 0.0001), and in the bran, decreased 8-isoprostane amounts (p < 0.0001), increased resolvin D1 levels (p < 0.005) and increased quantity of total n-3 PUFAs (p < 0.05). Furthermore, total brain n-3 PUFA levels were associated with disease severity (r = -0.562, p = 0.0001), resolvin D1 (r = 0.712, p < 0.0001), and 8-isoprostane brain levels (r = -0.690, p < 0.0001). For the first time in a natural model of KD, brain levels of n-3 PUFAs are shown to determine disease severity and to be involved in the peroxidation of brain PUFAs as well as in the production of pro-resolving lipid mediators. It is also shown that dietary supplementation with n-3 PUFAs leads to a slowing of the phenotypic presentation of the disease and restoration of lipid mediator production.

Keywords:  Krabbe disease; brain; fatty acid profile; isoprostanes; omega-3 PUFA; omega-3 enriched diet; resolvins

DOI:  https://doi.org/10.3390/ijms25137149
bioRxiv. 2024 Jun 28. pii: 2023.09.05.556135. [Epub ahead of print]

Single-cell atlas of ABCA7 loss-of-function reveals impaired neuronal respiration via choline-dependent lipid imbalances.

Djuna von Maydell, Shannon Wright, Julia Maeve Bonner, Colin Staab, Andrea Spitaleri, Liwang Liu, Ping-Chieh Pao, Chung Jong Yu, Aine Ni Scannail, Mingpei Li, Carles A Boix, Hansruedi Mathys, Guillaume Leclerc, Gloria Suella Menchaca, Gwyneth Welch, Agnese Graziosi, Noelle Leary, George Samaan, Manolis Kellis, Li-Huei Tsai.

Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase the risk of Alzheimer's disease (odds ratio ∼2), yet the pathogenic mechanisms and the neural cell types affected by these variants remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 human post-mortem samples from the prefrontal cortex of 12 ABCA7 LoF carriers and 24 matched non-carrier control individuals. ABCA7 LoF was associated with gene expression changes in all major cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed transcriptional changes related to lipid metabolism, mitochondrial function, cell cycle-related pathways, and synaptic signaling. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers), indicating that findings from our study may extend to large portions of the at-risk population. Consistent with ABCA7's function as a lipid exporter, lipidomic analysis of isogenic iPSC-derived neurons (iNs) revealed profound intracellular triglyceride accumulation in ABCA7 LoF, which was accompanied by a relative decrease in phosphatidylcholine abundance. Metabolomic and biochemical analyses of iNs further indicated that ABCA7 LoF was associated with disrupted mitochondrial bioenergetics that suggested impaired lipid breakdown by uncoupled respiration. Treatment of ABCA7 LoF iNs with CDP-choline (a rate-limiting precursor of phosphatidylcholine synthesis) reduced triglyceride accumulation and restored mitochondrial function, indicating that ABCA7 LoF-induced phosphatidylcholine dyshomeostasis may directly disrupt mitochondrial metabolism of lipids. Treatment with CDP-choline also rescued intracellular amyloid β -42 levels in ABCA7 LoF iNs, further suggesting a link between ABCA7 LoF metabolic disruptions in neurons and AD pathology. This study provides a detailed transcriptomic atlas of ABCA7 LoF in the human brain and mechanistically links ABCA7 LoF-induced lipid perturbations to neuronal energy dyshomeostasis. In line with a growing body of evidence, our study highlights the central role of lipid metabolism in the etiology of Alzheimer's disease.

DOI: https://doi.org/10.1101/2023.09.05.556135
Biochemistry. 2024 Jul 10.

A Facile LC-MS Method for Profiling Cholesterol and Cholesteryl Esters in Mammalian Cells and Tissues.

Aakash Chandramouli, Siddhesh S Kamat.

Cholesterol is central to mammalian lipid metabolism and serves many critical functions in the regulation of diverse physiological processes. Dysregulation in cholesterol metabolism is causally linked to numerous human diseases, and therefore, in vivo, the concentrations and flux of cholesterol and cholesteryl esters (fatty acid esters of cholesterol) are tightly regulated. While mass spectrometry has been an analytical method of choice for detecting cholesterol and cholesteryl esters in biological samples, the hydrophobicity, chemically inert nature, and poor ionization of these neutral lipids have often proved a challenge in developing lipidomics compatible liquid chromatography-mass spectrometry (LC-MS) methods to study them. To overcome this problem, here, we report a reverse-phase LC-MS method that is compatible with existing high-throughput lipidomics strategies and capable of identifying and quantifying cholesterol and cholesteryl esters from mammalian cells and tissues. Using this sensitive yet robust LC-MS method, we profiled different mammalian cell lines and tissues and provide a comprehensive picture of cholesterol and cholesteryl esters content in them. Specifically, among cholesteryl esters, we find that mammalian cells and tissues largely possess monounsaturated and polyunsaturated variants. Taken together, our lipidomics compatible LC-MS method to study this lipid class opens new avenues in understanding systemic and tissue-level cholesterol metabolism under various physiological conditions.

DOI: https://doi.org/10.1021/acs.biochem.4c00160
Methods Mol Biol. 2024 ;2816 193-204

Diacylglycerol Signaling in Retinal Ganglion Cells.

Ishan Chaplot, Isabella Moceri, Maria D Cabrera Gonzalez, Sanjoy K Bhattacharya.

  With impaired retinal ganglion cell (RGC) function and eventual RGC death, there is a heightened risk of experiencing glaucoma-induced blindness or other optic neuropathies. Poor RGC efficiency leads to limited transmission of visual signals between the retina and the brain by RGC axons. Increased focus on studying lipid messengers found in neurons such as endocannabinoids (eCBs) has importance due to their potential axonal pathway regenerative properties. 2-Arachidonoylglycerol (2-AG), a common eCB, is synthesized from an sn-1 hydrolysis reaction between diacylglycerol (DAG) and diacylglycerol lipase (DAGL). Examination of DAG production allows for future downstream analysis in relation to DAGL functionality. Here, we describe protocol guidelines for extracting RGCs from mouse retinas and subsequent mass spectrometry analysis of the DAG content present within the RGCs.

Keywords:  Axon regeneration; Diacylglycerol; Diacylglycerol signaling; Mass spectrometry; Retinal ganglion cells

DOI:  https://doi.org/10.1007/978-1-0716-3902-3_18
Front Cell Neurosci. 2024 ;18 1403734

Brain organoid as a model to study the role of mitochondria in neurodevelopmental disorders: achievements and weaknesses.

Raquel Coronel, Enrique García-Moreno, Emilio Siendones, Maria J Barrero, Beatriz Martínez-Delgado, Carlos Santos-Ocaña, Isabel Liste, M V Cascajo-Almenara.

  Mitochondrial diseases are a group of severe pathologies that cause complex neurodegenerative disorders for which, in most cases, no therapy or treatment is available. These organelles are critical regulators of both neurogenesis and homeostasis of the neurological system. Consequently, mitochondrial damage or dysfunction can occur as a cause or consequence of neurodevelopmental or neurodegenerative diseases. As genetic knowledge of neurodevelopmental disorders advances, associations have been identified between genes that encode mitochondrial proteins and neurological symptoms, such as neuropathy, encephalomyopathy, ataxia, seizures, and developmental delays, among others. Understanding how mitochondrial dysfunction can alter these processes is essential in researching rare diseases. Three-dimensional (3D) cell cultures, which self-assemble to form specialized structures composed of different cell types, represent an accessible manner to model organogenesis and neurodevelopmental disorders. In particular, brain organoids are revolutionizing the study of mitochondrial-based neurological diseases since they are organ-specific and model-generated from a patient's cell, thereby overcoming some of the limitations of traditional animal and cell models. In this review, we have collected which neurological structures and functions recapitulate in the different types of reported brain organoids, focusing on those generated as models of mitochondrial diseases. In addition to advancements in the generation of brain organoids, techniques, and approaches for studying neuronal structures and physiology, drug screening and drug repositioning studies performed in brain organoids with mitochondrial damage and neurodevelopmental disorders have also been reviewed. This scope review will summarize the evidence on limitations in studying the function and dynamics of mitochondria in brain organoids.

Keywords:  3D cultures; drug repurposing; high-throughput screening; mitochondrial diseases; neurodevelopmental disorders; organoid; spheroids

DOI:  https://doi.org/10.3389/fncel.2024.1403734
Methods Enzymol. 2024 ;pii: S0076-6879(24)00121-6. [Epub ahead of print]700 217-234

Using lipid binding proteins and advanced microscopy to study lipid domains.

Nario Tomishige, Kohta Takahashi, Brigitte Pollet, Ludovic Richert, Yves Mély, Toshihide Kobayashi.

  Sphingomyelin is postulated to form clusters with glycosphingolipids, cholesterol and other sphingomyelin molecules in biomembranes through hydrophobic interaction and hydrogen bonds. These clusters form submicron size lipid domains. Proteins that selectively binds sphingomyelin and/or cholesterol are useful to visualize the lipid domains. Due to their small size, visualization of lipid domains requires advanced microscopy techniques in addition to lipid binding proteins. This Chapter describes the method to characterize plasma membrane sphingomyelin-rich and cholesterol-rich lipid domains by quantitative microscopy. This Chapter also compares different permeabilization methods to visualize intracellular lipid domains.

Keywords:  Cholesterol; FLIM-FRET; Lipid probe; Sphingomyelin

DOI:  https://doi.org/10.1016/bs.mie.2024.03.026
Anal Chem. 2024 Jul 12.

Visualization of Phospholipid Synthesis on Tissue Sections Using Functional Mass Spectrometry Imaging.

Taiga Iwama, Kuniyuki Kano, Hiroki Kawana, Hideo Shindou, Takao Shimizu, Nozomu Kono, Junken Aoki.

Functional mass spectrometry imaging (fMSI) is a potent tool for elucidating the spatial distribution of enzyme activities in tissues at high resolution. In this study, we applied fMSI to probe the intricate biosynthesis of phospholipids, which exist as thousands of molecular species in tissues and exhibit a unique distribution specific to cell type. By using deuterium- and 13C-labeled substrates, we visualized the activities of key enzymes involved in phospholipid synthesis, including glycerol 3-phosphate acyltransferase (GPAT), lysophosphatidic acid acyltransferases (LPAAT), lysophospholipid acyltransferases (LPLAT), and long-chain acyl-CoA synthetase (ACSL). Additionally, we were able to visualize a two-step sequential enzyme reaction involving ACSL and LPLAT. This novel approach unveiled significant variations in enzyme activity distribution depending on the type of fatty acids used as substrates. It will also help to reveal the mechanisms underlying the formation of numerous phospholipid species.

DOI: https://doi.org/10.1021/acs.analchem.4c01219
Mol Cell. 2024 Jun 28. pii: S1097-2765(24)00512-4. [Epub ahead of print]

Hexokinase 1 forms rings that regulate mitochondrial fission during energy stress.

Johannes Pilic, Benjamin Gottschalk, Benjamin Bourgeois, Hansjörg Habisch, Zhanat Koshenov, Furkan E Oflaz, Yusuf C Erdogan, Seyed M Miri, Esra N Yiğit, Mehmet Ş Aydın, Gürkan Öztürk, Emrah Eroglu, Varda Shoshan-Barmatz, Tobias Madl, Wolfgang F Graier, Roland Malli.

  Metabolic enzymes can adapt during energy stress, but the consequences of these adaptations remain understudied. Here, we discovered that hexokinase 1 (HK1), a key glycolytic enzyme, forms rings around mitochondria during energy stress. These HK1-rings constrict mitochondria at contact sites with the endoplasmic reticulum (ER) and mitochondrial dynamics protein (MiD51). HK1-rings prevent mitochondrial fission by displacing the dynamin-related protein 1 (Drp1) from mitochondrial fission factor (Mff) and mitochondrial fission 1 protein (Fis1). The disassembly of HK1-rings during energy restoration correlated with mitochondrial fission. Mechanistically, we identified that the lack of ATP and glucose-6-phosphate (G6P) promotes the formation of HK1-rings. Mutations that affect the formation of HK1-rings showed that HK1-rings rewire cellular metabolism toward increased TCA cycle activity. Our findings highlight that HK1 is an energy stress sensor that regulates the shape, connectivity, and metabolic activity of mitochondria. Thus, the formation of HK1-rings may affect mitochondrial function in energy-stress-related pathologies.

Keywords:  ER-mitochondria contact sites; energy stress; glucose starvation; glycolysis; hexokinase; live-cell imaging; mitochondrial constriction; mitochondrial fission; non-catalytic functions; protein cluster

DOI:  https://doi.org/10.1016/j.molcel.2024.06.009
Cell Mol Life Sci. 2024 Jul 08. 81(1): 293

Short-chain fatty acids suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in experimental autoimmune encephalomyelitis mice.

Xiuli Lin, Yufeng Peng, Zhimei Guo, Wuhui He, Wenyuan Guo, Junmin Feng, Lin Lu, Qin Liu, Pingyi Xu.

  The function of astrocytes in response to gut microbiota-derived signals has an important role in the pathophysiological processes of central nervous system (CNS) diseases. However, the specific effects of microbiota-derived metabolites on astrocyte activation have not been elucidated yet. Experimental autoimmune encephalomyelitis (EAE) was induced in female C57BL/6 mice as a classical MS model. The alterations of gut microbiota and the levels of short-chain fatty acids (SCFAs) were assessed after EAE induction. We observed that EAE mice exhibit low levels of Allobaculum, Clostridium_IV, Clostridium_XlVb, Lactobacillus genera, and microbial-derived SCFAs metabolites. SCFAs supplementation suppressed astrocyte activation by increasing the level of tryptophan (Trp)-derived AhR ligands that activating the AhR. The beneficial effects of SCFAs supplementation on the clinical scores, histopathological alterations, and the blood brain barrier (BBB)-glymphatic function were abolished by intracisterna magna injection of AAV-GFAP-shAhR. Moreover, SCFAs supplementation suppressed the loss of AQP4 polarity within astrocytes in an AhR-dependent manner. Together, SCFAs potentially suppresses astrocyte activation by amplifying Trp-AhR-AQP4 signaling in EAE mice. Our study demonstrates that SCFAs supplementation may serve as a viable therapy for inflammatory disorders of the CNS.

Keywords:  Astrocytes; BBB-glymphatic system; Multiple sclerosis; Short-chain fatty acids; Trp-AhR-AQP4 signaling

DOI:  https://doi.org/10.1007/s00018-024-05332-x
Methods Mol Biol. 2024 ;2816 35-40

Analysis of Sphingosine and Sphinganine from the Aqueous Humor for Signaling Studies Using Ultrahigh-Performance Liquid Chromatography-Mass Spectrometry.

Meher A Saleem, Molly Kennedy, Omar Badla, Emily J Neag, Sanjoy K Bhattacharya.

  Sphingolipids, including sphingosine and sphinganine, are one of the major classes of lipids. They serve as constituents of cell membranes and lipid rafts and aid in the performance of cell-cell communication and adhesion. Abnormal levels of sphingolipids in the aqueous humor can indicate impaired sphingolipid metabolism and associated ocular pathologies. Sphingolipids can be extracted from the aqueous humor by the methyl-tert-butyl ether (MTBE) lipid extraction method and subsequently analyzed by liquid chromatography-mass spectrometry (LC-MS). This chapter describes a modified protocol for an MTBE lipid extraction from the aqueous humor, followed by analysis with ultrahigh-performance liquid chromatography-mass spectrometry (UHPLC-MS).

Keywords:  Aqueous humor; LC; LC-MS; Lipid extraction; Lipidomics; Liquid chromatography; MS; MTBE; Mass spectrometry; Sphinganine; Sphingolipidomics; Sphingolipids; Sphingosine; UHPLC; UHPLC-MS; Ultrahigh-performance liquid chromatography

DOI:  https://doi.org/10.1007/978-1-0716-3902-3_4
JIMD Rep. 2024 Jul;65(4): 280-294

Galactokinase 1 is the source of elevated galactose-1-phosphate and cerebrosides are modestly reduced in a mouse model of classic galactosemia.

Linley Mangini, Roger Lawrence, Manuel E Lopez, Timothy C Graham, Christopher R Bauer, Hang Nguyen, Cheng Su, John Ramphal, Brett E Crawford, Tom A Hartl.

  Classic galactosemia (CG) arises from loss-of-function mutations in the Galt gene, which codes for the enzyme galactose-1-phosphate uridylyltransferase (GALT), a central component in galactose metabolism. The neonatal fatality associated with CG can be prevented by galactose dietary restriction, but for decades it has been known that limiting galactose intake is not a cure and patients often have lasting complications. Even on a low-galactose diet, GALT's substrate galactose-1-phosphate (Gal1P) is elevated and one hypothesis is that elevated Gal1P is a driver of pathology. Here we show that Gal1P levels were elevated above wildtype (WT) in Galt mutant mice, while mice doubly mutant for Galt and the gene encoding galactokinase 1 (Galk1) had normal Gal1P levels. This indicates that GALK1 is necessary for the elevated Gal1P in CG. Another hypothesis to explain the pathology is that an inability to metabolize galactose leads to diminished or disrupted galactosylation of proteins or lipids. Our studies reveal that levels of a subset of cerebrosides-galactosylceramide 24:1, sulfatide 24:1, and glucosylceramide 24:1-were modestly decreased compared to WT. In contrast, gangliosides were unaltered. The observed reduction in these 24:1 cerebrosides may be relevant to the clinical pathology of CG, since the cerebroside galactosylceramide is an important structural component of myelin, the 24:1 species is the most abundant in myelin, and irregularities in white matter, of which myelin is a constituent, have been observed in patients with CG. Therefore, impaired cerebroside production may be a contributing factor to the brain damage that is a common clinical feature of the human disease.

Keywords:  cerebroside; galactokinase 1 (GALK1); galactosemia; galactose‐1‐phosphate uridylyltransferase (GALT); galactosylceramide; myelin

DOI:  https://doi.org/10.1002/jmd2.12438
J Neurochem. 2024 Jul 12.

Cell type-specific and subcellular expression of phospholipid phosphatase-related proteins to modulate lyso-phosphatidic acid synaptic signaling in the developing and adult CNS.

Alexandra Polyzou, Joachim Fuchs, Cristina Kroon, Androniki Kotoula, Foteini Delis, Paul Turko, Katerina Antoniou, Britta Eickholt, George Leondaritis.

  Lysophosphatidic acid (LPA) is a bioactive phospholipid that participates in critical processes in neural development and adult brain function and is implicated in various pathophysiological conditions. Along with its six well-characterized receptors, atypical regulators of LPA signaling have also been suggested, including phospholipid phosphatase-related proteins (PLPPRs). PLPPRs have been mostly studied in the developing brain where they control LPA-dependent axon guidance, cortical network hyperexcitability, and glutamatergic neurotransmission. PLPPR4 and PLPPR3 represent two closely related proteins reported to localize predominantly in dendrites and axons, respectively, and differ in their developmental expression patterns. Herein, we have revised the expression patterns of PLPPRs in the cerebellum, dorsal and ventral hippocampus, prefrontal cortex (PFC), nucleus accumbens, and striatum during development and in the adult using quantitative PCR. Expression patterns of Plppr2,4 and 5 were consistent with previous studies, whereas Plppr3 and Plppr1 exhibited a unique expression profile in nucleus accumbens (NAc) and striatum in later developmental and adult stages, which we verified at the protein level for PLPPR3. To investigate neuron type-specific expression at the single cell level, we developed a bioinformatic tool to analyze recent single-cell RNA-sequencing data in the cerebral cortex and hippocampus of adult mice. Our analysis revealed a widespread but also selective adult neuron-type expression with higher expression levels of Plppr3, Plppr1, and Plppr5 in GABAergic and Plppr4 and Plppr2 in glutamatergic neurons. PLPPR4 has been identified as a post-synaptic modulator of LPA levels in glutamatergic synapses operating via an uptake mechanism, to control LPA-dependent cortical network hyperexcitability. Using subcellular fractionation experiments, we found that both PLPPR4 and PLPPR3 are co-expressed in adult synaptosomal membranes. Furthermore, flow cytometry experiments in HEK293 cells showed comparable LPA uptake by PLPPR4 and PLPPR3, whereas PLPRR3, but not PLPPR4, induced also uptake of monoacylglycerol, the dephosphorylation product of LPA. We propose that synaptic LPA may be subject to both pre-synaptic and post-synaptic mechanisms of regulation by PLPPRs in addition to LPARs in developing and adult synapses.

Keywords:  PRG; bioactive lipid; lysophosphatidic acid; plasticity‐related gene; synapse

DOI:  https://doi.org/10.1111/jnc.16169
Neurochem Res. 2024 Jul 11.

Luteolin Mitigates D-Galactose-Induced Brain Ageing in Rats: SIRT1-Mediated Neuroprotection.

Reham L Younis, Rehab M El-Gohary, Asmaa A Ghalwash, Islam Ibrahim Hegab, Maram M Ghabrial, Azza M Aboshanady, Raghad A Mostafa, Alaa H Abd El-Azeem, Eman E Farghal, Asmaa A E Belal, Haidy Khattab.

  Luteolin is an essential natural polyphenol found in a variety of plants. Numerous studies have supported its protective role in neurodegenerative diseases, yet the research for its therapeutic utility in D-galactose (D-gal)-induced brain ageing is still lacking. In this study, the potential neuroprotective impact of luteolin against D-gal-induced brain ageing was explored. Forty rats were randomly divided into four groups: control, luteolin, D-gal, and luteolin-administered D-gal groups. All groups were subjected to behavioural, cholinergic function, and hippocampal mitochondrial respiration assessments. Hippocampal oxidative, neuro-inflammatory, senescence and apoptotic indicators were detected. Gene expressions of SIRT1, BDNF, and RAGE were assessed. Hippocampal histopathological studies, along with GFAP and Ki67 immunoreactivity, were performed. Our results demonstrated that luteolin effectively alleviated D-gal-induced cognitive impairment and reversed cholinergic abnormalities. Furthermore, luteolin administration substantially mitigated hippocampus oxidative stress, mitochondrial dysfunction, neuro-inflammation, and senescence triggered by D-gal. Additionally, luteolin treatment considerably attenuated neuronal apoptosis and upregulated hippocampal SIRT1 mRNA expression. In conclusion, our findings revealed that luteolin administration attenuated D-gal-evoked brain senescence, improving mitochondrial function and enhancing hippocampal neuroregeneration in an ageing rat model through its antioxidant, senolytic, anti-inflammatory, and anti-apoptotic impacts, possibly due to upregulation of SIRT1. Luteolin could be a promising therapeutic modality for brain aging-associated abnormalities.

Keywords:  AGE/RAGE axis; Brain ageing; D-galactose; Luteolin; Mitochondrial dysfunction; SIRT1

DOI:  https://doi.org/10.1007/s11064-024-04203-y
Acta Histochem Cytochem. 2024 Jun 28. 57(3): 89-100

Purinosomes and Purine Metabolism in Mammalian Neural Development: A Review.

Seiya Yamada, Tomoya Mizukoshi, Ayaka Sato, Shin-Ichi Sakakibara.

  Neural stem/progenitor cells (NSPCs) in specific brain regions require precisely regulated metabolite production during critical development periods. Purines-vital components of DNA, RNA, and energy carriers like ATP and GTP-are crucial metabolites in brain development. Purine levels are tightly controlled through two pathways: de novo synthesis and salvage synthesis. Enzymes driving de novo pathway are assembled into a large multienzyme complex termed the "purinosome." Here, we review purine metabolism and purinosomes as spatiotemporal regulators of neural development. Notably, around postnatal day 0 (P0) during mouse cortical development, purine synthesis transitions from the de novo pathway to the salvage pathway. Inhibiting the de novo pathway affects mTORC1 pathway and leads to specific forebrain malformations. In this review, we also explore the importance of protein-protein interactions of a newly identified NSPC protein-NACHT and WD repeat domain-containing 1 (Nwd1)-in purinosome formation. Reduced Nwd1 expression disrupts purinosome formation, impacting NSPC proliferation and neuronal migration, resulting in periventricular heterotopia. Nwd1 interacts directly with phosphoribosylaminoimidazole-succinocarboxamide synthetase (PAICS), an enzyme involved in de novo purine synthesis. We anticipate this review will be valuable for researchers investigating neural development, purine metabolism, and protein-protein interactions.

Keywords:  Nwd1; neural development; neural stem/progenitor cells (NSPCs); purine metabolism; purinosome

DOI:  https://doi.org/10.1267/ahc.24-00027
Sci Adv. 2024 Jul 12. 10(28): eadi4746

27-Hydroxycholesterol acts on estrogen receptor α expressed by POMC neurons in the arcuate nucleus to modulate feeding behavior.

Hui Ye, Xiaohua Yang, Bing Feng, Pei Luo, Valeria C Torres Irizarry, Leslie Carrillo-Sáenz, Meng Yu, Yongjie Yang, Benjamin P Eappen, Marcos David Munoz, Nirali Patel, Sarah Schaul, Lucas Ibrahimi, Penghua Lai, Xinyue Qi, Yuliang Zhou, Maya Kota, Devin Dixit, Madeline Mun, Chong Wee Liew, Yuwei Jiang, Chunmei Wang, Yanlin He, Pingwen Xu.

Oxysterols are metabolites of cholesterol that regulate cholesterol homeostasis. Among these, the most abundant oxysterol is 27-hydroxycholesterol (27HC), which can cross the blood-brain barrier. Because 27HC functions as an endogenous selective estrogen receptor modulator, we hypothesize that 27HC binds to the estrogen receptor α (ERα) in the brain to regulate energy balance. Supporting this view, we found that delivering 27HC to the brain reduced food intake and activated proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus (POMCARH) in an ERα-dependent manner. In addition, we observed that inhibiting brain ERα, deleting ERα in POMC neurons, or chemogenetic inhibition of POMCARH neurons blocked the anorexigenic effects of 27HC. Mechanistically, we further revealed that 27HC stimulates POMCARH neurons by inhibiting the small conductance of the calcium-activated potassium (SK) channel. Together, our findings suggest that 27HC, through its interaction with ERα and modulation of the SK channel, inhibits food intake as a negative feedback mechanism against a surge in circulating cholesterol.

DOI: https://doi.org/10.1126/sciadv.adi4746
J Inherit Metab Dis. 2024 Jul 12.

Citrin deficiency-The East-side story.

Johannes Häberle.

  Citrin deficiency (CD) is a complex metabolic condition due to defects in SLC25A13 encoding citrin, an aspartate/glutamate carrier located in the mitochondrial inner membrane. The condition was first described in Japan and other East Asian countries in patients who were thought to suffer from classical citrullinemia type 1, and was therefore classified as a urea cycle disorder. With an improved understanding of its molecular basis, it became apparent that a defect of citrin is primarily affecting the malate-aspartate shuttle with however multiple secondary effects on many central metabolic pathways including glycolysis, gluconeogenesis, de novo lipogenesis and ureagenesis. In the meantime, it became also clear that CD must be considered as a global disease with patients identified in many parts of the world and affected by SLC25A13 genotypes different from those known in East Asian populations. The present short review summarizes the (hi)story of this complex metabolic condition and tries to explain the relevance of including CD as a differential diagnosis in neonates and infants with cholestasis and in (not only adult) patients with hyperammonemia of unknown origin with subsequent impact on the emergency management.

Keywords:  adult citrullinemia; brain edema; cholestasis; fatty liver disease; hypercitrullinemia

DOI:  https://doi.org/10.1002/jimd.12772