bims-medebr 2023-08-27 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023–08–27
33 papers selected by
Regina F. Fernández, Johns Hopkins University

Hypometabolism, Alzheimer's Disease, and Possible Therapeutic Targets: An Overview.
Alterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis.
APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids.
AMPKα1 Deficiency in Astrocytes from a Rat Model of ALS Is Associated with an Altered Metabolic Resilience.
Hexosamine Biosynthetic Pathway and O-GlcNAc cycling of Glucose Metabolism in Brain Function and Disease.
Aerobic Exercise Facilitates the Nuclear Translocation of SREBP2 by Activating AKT/SEC24D to Contribute Cholesterol Homeostasis for Improving Cognition in APP/PS1 Mice.
MALDI mass spectrometry imaging discloses the decline of sulfoglycosphingolipid and glycerophosphoinositol species in the brain regions related to cognition in a mouse model of Alzheimer's disease.
Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction.
Pharmacological inhibition of FABP7 by MF 6 counteracts cerebellum dysfunction in an experimental multiple system atrophy mouse model.
Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV.
Association of the fibronectin type III domain-containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans.
Lipids and Secretory Vesicle Exocytosis.
Accelerated aging in mice with astrocytic redox imbalance as a consequence of SOD2 deletion.
Mechanisms of Modulation of Mitochondrial Architecture.
Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination.
Lipid Metabolism Disorder in Cerebrospinal Fluid Related to Parkinson's Disease.
The Impacts of Slc19a3 Deletion and Intestinal SLC19A3 Insertion on Thiamine Distribution and Brain Metabolism in the Mouse.
Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.
Postnatal Overfeeding in Rodents Induces a Neurodevelopment Delay and Anxious-like Behaviour Accompanied by Sex- and Brain-Region-Specific Synaptic and Metabolic Changes.
Long-Term Treatment of Lipoprotein Lipase Deficiency with Medium-Chain Triglyceride-Enriched Diet: A Case Series.
Distribution of Monocarboxylate Transporters in Brain and Choroid Plexus Epithelium.
Mechanistic understanding of bacterial FAALs and the role of their homologs in eukaryotes.
Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.
An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis.
Association between gene expression and functional-metabolic architecture in Parkinson's disease.
Glycometabolic Reprogramming of Microglia in Neurodegenerative Diseases: Insights from Neuroinflammation.
Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury.
Comparative Metabolomics in Single Ventricle Patients after Fontan Palliation: A Strong Case for a Targeted Metabolic Therapy.
Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer's disease pathology in the 5xFAD mouse.
A Novel HSPB1S139F Mouse Model of Charcot-Marie-Tooth Disease.
Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.
The pentose phosphate pathway in health and disease.
Ferroptosis and mitochondrial dysfunction in acute central nervous system injury.

Cells. 2023 Aug 08. pii: 2019. [Epub ahead of print]12(16):

Hypometabolism, Alzheimer's Disease, and Possible Therapeutic Targets: An Overview.

Snehal Raut, Aditya Bhalerao, Michael Powers, Minelly Gonzalez, Salvatore Mancuso, Luca Cucullo.

  The brain is a highly dynamic organ that requires a constant energy source to function normally. This energy is mostly supplied by glucose, a simple sugar that serves as the brain's principal fuel source. Glucose transport across the blood-brain barrier (BBB) is primarily controlled via sodium-independent facilitated glucose transport, such as by glucose transporter 1 (GLUT1) and 3 (GLUT3). However, other glucose transporters, including GLUT4 and the sodium-dependent transporters SGLT1 and SGLT6, have been reported in vitro and in vivo. When the BBB endothelial layer is crossed, neurons and astrocytes can absorb the glucose using their GLUT1 and GLUT3 transporters. Glucose then enters the glycolytic pathway and is metabolized into adenosine triphosphate (ATP), which supplies the energy to support cellular functions. The transport and metabolism of glucose in the brain are impacted by several medical conditions, which can cause neurological and neuropsychiatric symptoms. Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, traumatic brain injury (TBI), schizophrenia, etc., are a few of the most prevalent disorders, characterized by a decline in brain metabolism or hypometabolism early in the course of the disease. Indeed, AD is considered a metabolic disorder related to decreased brain glucose metabolism, involving brain insulin resistance and age-dependent mitochondrial dysfunction. Although the conventional view is that reduced cerebral metabolism is an effect of neuronal loss and consequent brain atrophy, a growing body of evidence points to the opposite, where hypometabolism is prodromal or at least precedes the onset of brain atrophy and the manifestation of clinical symptoms. The underlying processes responsible for these glucose transport and metabolic abnormalities are complicated and remain poorly understood. This review article provides a comprehensive overview of the current understanding of hypometabolism in AD and potential therapeutic targets.

Keywords:  Alzheimer’s disease; blood–brain barrier; glucose metabolism; glucose transporter; glucose uptake; oxidative stress

DOI:  https://doi.org/10.3390/cells12162019
Int J Mol Sci. 2023 Aug 18. pii: 12912. [Epub ahead of print]24(16):

Alterations of Oligodendrocyte and Myelin Energy Metabolism in Multiple Sclerosis.

Eneritz López-Muguruza, Carlos Matute.

  Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration. Oligodendrocytes play a vital role in maintaining the integrity of myelin, the protective sheath around nerve fibres essential for efficient signal transmission. However, in MS, oligodendrocytes become dysfunctional, leading to myelin damage and axonal degeneration. Emerging evidence suggests that metabolic changes, including mitochondrial dysfunction and alterations in glucose and lipid metabolism, contribute significantly to the pathogenesis of MS. Mitochondrial dysfunction is observed in both immune cells and oligodendrocytes within the CNS of MS patients. Impaired mitochondrial function leads to energy deficits, affecting crucial processes such as impulse transmission and axonal transport, ultimately contributing to neurodegeneration. Moreover, mitochondrial dysfunction is linked to the generation of reactive oxygen species (ROS), exacerbating myelin damage and inflammation. Altered glucose metabolism affects the energy supply required for oligodendrocyte function and myelin synthesis. Dysregulated lipid metabolism results in changes to the composition of myelin, affecting its stability and integrity. Importantly, low levels of polyunsaturated fatty acids in MS are associated with upregulated lipid metabolism and enhanced glucose catabolism. Understanding the intricate relationship between these mechanisms is crucial for developing targeted therapies to preserve myelin and promote neurological recovery in individuals with MS. Addressing these metabolic aspects may offer new insights into potential therapeutic strategies to halt disease progression and improve the quality of life for MS patients.

Keywords:  axonal damage; demyelination; dysmyelination; lipids; mitochondria; neurodegeneration; progressive multiple sclerosis; remyelination; repair

DOI:  https://doi.org/10.3390/ijms241612912
Stem Cell Res Ther. 2023 Aug 21. 14(1): 214

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids.

Jing Zhao, Tadafumi C Ikezu, Wenyan Lu, Jesse R Macyczko, Yonghe Li, Laura J Lewis-Tuffin, Yuka A Martens, Yingxue Ren, Yiyang Zhu, Yan W Asmann, Nilüfer Ertekin-Taner, Takahisa Kanekiyo, Guojun Bu.

   BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types.
METHODS: We generated three-dimensional (3-D) cerebral organoids from human parental iPSC lines and its isogenic APOE-deficient (APOE-/-) iPSC line. To elucidate the cell-type-specific effects of APOE deficiency in the cerebral organoids, we performed scRNA-seq in the parental and APOE-/- cerebral organoids at Day 90.
RESULTS: We show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single-cell RNA sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the eukaryotic initiation factor 2 (EIF2) signaling pathway as these events were alleviated by the treatment of an integrated stress response inhibitor (ISRIB). APOE deletion also leads to activation of the Wnt/β-catenin signaling pathway with concomitant decrease of secreted frizzled-related protein 1 (SFRP1) expression in glia cells. Importantly, the critical role of apoE in cell-type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3.
CONCLUSIONS: Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms.

Keywords:  Apolipoprotein E; Cerebral organoid; Cholesterol biosynthesis; Neural differentiation; scRNA-seq

DOI:  https://doi.org/10.1186/s13287-023-03444-y
Biomolecules. 2023 Jul 28. pii: 1183. [Epub ahead of print]13(8):

AMPKα1 Deficiency in Astrocytes from a Rat Model of ALS Is Associated with an Altered Metabolic Resilience.

Inês Belo do Nascimento, Gamze Ates, Nathalie Desmet, Pauline Beckers, Ann Massie, Emmanuel Hermans.

  Alterations in the activity of the regulator of cell metabolism AMP-activated protein kinase (AMPK) have been reported in motor neurons from patients and animal models of amyotrophic lateral sclerosis (ALS). Considering the key role played by astrocytes in modulating energy metabolism in the nervous system and their compromised support towards neurons in ALS, we examined whether a putative alteration in AMPK expression/activity impacted astrocytic functions such as their metabolic plasticity and glutamate handling capacity. We found a reduced expression of AMPK mRNA in primary cultures of astrocytes derived from transgenic rats carrying an ALS-associated mutated superoxide dismutase (hSOD1G93A). The activation of AMPK after glucose deprivation was reduced in hSOD1G93A astrocytes compared to non-transgenic. This was accompanied by a lower increase in ATP levels and increased vulnerability to this insult, although the ATP production rate did not differ between the two cell types. Furthermore, soliciting the activity of glutamate transporters was found to induce similar AMPK activity in these cells. However, manipulation of AMPK activity did not influence glutamate transport. Together, these results suggest that the altered AMPK responsiveness in ALS might be context dependent and may compromise the metabolic adaptation of astrocytes in response to specific cellular stress.

Keywords:  AMPK; ATP; glutamate transport; metabolic stress

DOI:  https://doi.org/10.3390/biom13081183
Am J Physiol Cell Physiol. 2023 Aug 21.

Hexosamine Biosynthetic Pathway and O-GlcNAc cycling of Glucose Metabolism in Brain Function and Disease.

Dong Yeol Kim, Jiwon Park, Inn-Oc Han.

  Impaired brain glucose metabolism is considered a hallmark of brain dysfunction and neurodegeneration. Disruption of the hexosamine biosynthetic pathway (HBP) and subsequent O-linked N-acetylglucosamine (O-GlcNAc) cycling has been identified as an emerging link between altered glucose metabolism and defects in the brain. Myriads of cytosolic and nuclear proteins in the nervous system are modified at serine or threonine residues with a single N-acetylglucosamine (O-GlcNAc) molecule by O-GlcNAc transferase (OGT), which can be removed by β-N-acetylglucosaminidase (O-GlcNAcase, OGA). Homeostatic regulation of O-GlcNAc cycling is important for maintenance of normal brain activity. While significant evidence linking dysregulated HBP metabolism and aberrant O-GlcNAc cycling to induction or progression of neuronal diseases has been obtained, the issue of whether altered O-GlcNAcylation is causal in brain pathogenesis remains uncertain. Elucidation of the specific functions and regulatory mechanisms of individual O-GlcNAcylated neuronal proteins in both normal and diseased states may facilitate the identification of novel therapeutic targets for various neuronal disorders. The information presented in this review highlights the importance of HBP/O-GlcNAcylation in the neuronal system and summarizes the roles and potential mechanisms of O-GlcNAcylated neuronal proteins in maintaining normal brain function and initiation and progression of neurological diseases.

Keywords:  Hexosamine biosynthetic pathway; Neurodegeneration; O-GlcNAcylation

DOI:  https://doi.org/10.1152/ajpcell.00191.2023
Int J Mol Sci. 2023 Aug 16. pii: 12847. [Epub ahead of print]24(16):

Aerobic Exercise Facilitates the Nuclear Translocation of SREBP2 by Activating AKT/SEC24D to Contribute Cholesterol Homeostasis for Improving Cognition in APP/PS1 Mice.

Zelin Hu, Yangqi Yuan, Zhen Tong, Meiqing Liao, Shunling Yuan, Weijia Wu, Yingzhe Tang, Yirong Wang, Changfa Tang, Wenfeng Liu.

  Impaired cholesterol synthesizing ability is considered a risk factor for the development of Alzheimer's disease (AD), as evidenced by reduced levels of key proteases in the brain that mediate cholesterol synthesis; however, cholesterol deposition has been found in neurons in tangles in the brains of AD patients. Although it has been shown that statins, which inhibit cholesterol synthesis, reduce the incidence of AD, this seems paradoxical for AD patients whose cholesterol synthesizing capacity is already impaired. In this study, we aimed to investigate the effects of aerobic exercise on cholesterol metabolism in the brains of APP/PS1 mice and to reveal the mechanisms by which aerobic exercise improves cognitive function in APP/PS1 mice. Our study demonstrates that the reduction of SEC24D protein, a component of coat protein complex II (COPII), is a key factor in the reduction of cholesterol synthesis in the brain of APP/PS1 mice. 12 weeks of aerobic exercise was able to promote the recovery of SEC24D protein levels in the brain through activation of protein kinase B (AKT), which in turn promoted the expression of mem-brane-bound sterol regulatory element-binding protein 2 (SREBP2) nuclear translocation and the expression of key proteases mediating cholesterol synthesis. Simultaneous aerobic exercise restored cholesterol transport capacity in the brain of APP/PS1 mice with the ability to efflux excess cholesterol from neurons and reduced neuronal lipid rafts, thereby reducing cleavage of the APP amyloid pathway. Our study emphasizes the potential of restoring intracerebral cholesterol homeostasis as a therapeutic strategy to alleviate cognitive impairment in AD patients.

Keywords:  Alzheimer’s disease; amyloid-beta; cholesterol; oxysterols; sterol regulatory element-binding protein-2

DOI:  https://doi.org/10.3390/ijms241612847
Talanta. 2023 Aug 01. pii: S0039-9140(23)00773-7. [Epub ahead of print]266(Pt 2): 125022

MALDI mass spectrometry imaging discloses the decline of sulfoglycosphingolipid and glycerophosphoinositol species in the brain regions related to cognition in a mouse model of Alzheimer's disease.

Qi Zhang, Yan Li, Ping Sui, Xue-Heng Sun, Yufei Gao, Chun-Yan Wang.

  Aging and neurodegenerative disease are accompanied by lipid perturbations in the brain. Understanding the changes in the contents and functional activity of lipids remains a challenge not only because of the many areas in which lipids perform bioactivities but also because of the technical limitations in identifying lipids and their metabolites. In the present study, we aimed to evaluate how brain lipids are altered in Alzheimer's disease (AD)-like pathology by using mass spectrometry imaging (MSI). The spatial distributions and relative abundances of lipids in the brains were compared between APP/PS1 mice and their age-matched wild-type (WT) mice by matrix-assisted laser desorption ionization (MALDI) MSI assays. The comparisons were correlated with the analysis using a spectrophotometric method to determine the relative contents of sulfatides in different brain regions. Significant changes of brain lipids between APP/PS1 and WT mice were identified: eight sulfoglycosphingolipid species, namely, sulfatides/sulfated hexosyl ceramides (ShexCer) and two glycerophosphoinositol (GroPIn) species, PI 36:4 and PI 38:4. The declines in the spatial distributions of these ShexCer and GroPIn species in the APP/PS1 mice brains were associated with learning- and memory-related brain regions. Compared with young WT mice, aged WT mice showed significant decreases in the levels of these ShexCer and GroPIn species. Our results provide technical clues for assessing the impact of brain lipid metabolism on the senescent and neurodegenerative brain. The decline in sulfatides and GroPIns may be crucial markers during brain senescence and AD pathology. Appropriate lipid complementation might be important potentials as a therapeutic strategy for AD.

Keywords:  Alzheimer's disease; Brain lipids homeostasis; Cognition-related brain regions; MALDI-MSI; Transgenic mouse

DOI:  https://doi.org/10.1016/j.talanta.2023.125022
J Mol Med (Berl). 2023 Aug 21.

Distinctive metabolic remodeling in TYMP deficiency beyond mitochondrial dysfunction.

Jixiang Du, Chao Zhang, Fuchen Liu, Xihan Liu, Dongdong Wang, Dandan Zhao, Guanghou Shui, Yuying Zhao, Chuanzhu Yan.

  Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is caused by mutations in the TYMP gene, which encodes thymidine phosphorylase (TP). As a cytosolic metabolic enzyme, TP defects affect biological processes that are thought to not be limited to the abnormal replication of mitochondrial DNA. This study aimed to elucidate the characteristic metabolic alterations and associated homeostatic regulation caused by TYMP deficiency. The pathogenicity of novel TYMP variants was evaluated in terms of clinical features, genetic analysis, and structural instability. We analyzed plasma samples from three patients with MNGIE; three patients with m.3243A > G mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS); and four healthy controls (HC) using both targeted and untargeted metabolomics techniques. Transcriptomics analysis and bioenergetic studies were performed on skin fibroblasts from participants in these three groups. A TYMP overexpression experiment was conducted to rescue the observed changes. Compared with controls, specific alterations in nucleosides, bile acids, and steroid metabolites were identified in the plasma of MNGIE patients. Comparable mitochondrial dysfunction was present in fibroblasts from patients with TYMP deficiency and in those from patients with the m.3243A > G mutation. Distinctively decreased sterol regulatory element binding protein (SREBP) regulated cholesterol metabolism and fatty acid (FA) biosynthesis as well as reduced FA degradation were revealed in fibroblasts with TYMP deficiency. The restoration of thymidine phosphorylase activity rescued the observed changes in MNGIE fibroblasts. Our findings indicated that more widespread metabolic disturbance may be caused by TYMP deficiency in addition to mitochondrial dysfunction, which expands our knowledge of the biochemical outcome of TYMP deficiency. KEY MESSAGES: Distinct metabolic profiles in patients with TYMP deficiency compared to those with m.3243A > G mutation. TYMP deficiency leads to a global disruption of nucleoside metabolism. Cholesterol and fatty acid metabolism are inhibited in individuals with MNGIE. TYMP is functionally related to SREBP-regulated pathways. Potential metabolite biomarkers that could be valuable clinical tools to improve the diagnosis of MNGIE.

Keywords:  Cholesterol metabolism; Fatty acid metabolism; MNGIE; Metabolomics; TYMP

DOI:  https://doi.org/10.1007/s00109-023-02358-9
Acta Pharmacol Sin. 2023 Aug 21.

Pharmacological inhibition of FABP7 by MF 6 counteracts cerebellum dysfunction in an experimental multiple system atrophy mouse model.

An Cheng, Wenbin Jia, David I Finkelstein, Nadia Stefanova, Haoyang Wang, Takuya Sasaki, Ichiro Kawahata, Kohji Fukunaga.

  Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disease characterized by the accumulation of misfolded α-synuclein (αSyn) in glial cells, leading to the formation of glial cytoplasmic inclusions (GCI). We previous found that glial fatty acid-binding protein 7 (FABP7) played a crucial role in alpha-synuclein (αSyn) aggregation and toxicity in oligodendrocytes, inhibition of FABP7 by a specific inhibitor MF 6 reduced αSyn aggregation and enhanced cell viability in cultured cell lines and mouse oligodendrocyte progenitor cells. In this study we investigated whether MF 6 ameliorated αSyn-associated pathological processes in PLP-hαSyn transgenic mice (PLP-αSyn mice), a wildly used MSA mouse model with overexpressing αSyn in oligodendroglia under the proteolipid protein (PLP) promoter. PLP-αSyn mice were orally administered MF6 (0.1, 1 mg ·kg-1 ·d-1) for 32 days starting from the age of 6 months. We showed that oral administration of MF 6 significantly improved motor function assessed in a pole test, and reduced αSyn aggregation levels in both cerebellum and basal ganglia of PLP-αSyn mice. Moreover, MF 6 administration decreased oxidative stress and inflammation levels, and improved myelin levels and Purkinje neuron morphology in the cerebellum. By using mouse brain tissue slices and αSyn aggregates-treated KG-1C cells, we demonstrated that MF 6 reduced αSyn propagation to Purkinje neurons and oligodendrocytes through regulating endocytosis. Overall, these results suggest that MF 6 improves cerebellar functions in MSA by inhibiting αSyn aggregation and propagation. We conclude that MF 6 is a promising compound that warrants further development for the treatment of MSA.

Keywords:  MF 6; Purkinje neuron; alpha-synuclein; cerebellum; multiple system atrophy; oligodendrocyte

DOI:  https://doi.org/10.1038/s41401-023-01138-y
Front Mol Neurosci. 2023 ;16 1215425

Brain cell type specific proteomics approach to discover pathological mechanisms in the childhood CNS disorder mucolipidosis type IV.

Madison Sangster, Sanjid Shahriar, Zachary Niziolek, Maria Carla Carisi, Michael Lewandowski, Bogdan Budnik, Yulia Grishchuk.

  Mucolipidosis IV (MLIV) is an ultra-rare, recessively inherited lysosomal disorder resulting from inactivating mutations in MCOLN1, the gene encoding the lysosomal cation channel TRPML1. The disease primarily affects the central nervous system (CNS) and manifests in the first year with cognitive and motor developmental delay, followed by a gradual decline in neurological function across the second decade of life, blindness, and premature death in third or fourth decades. Brain pathology manifestations in MLIV are consistent with hypomyelinating leukodystrophy with brain iron accumulation. Presently, there are no approved or investigational therapies for MLIV, and pathogenic mechanisms remain largely unknown. The MLIV mouse model, Mcoln1-/- mice, recapitulates all major manifestations of the human disease. Here, to better understand the pathological mechanisms in the MLIV brain, we performed cell type specific LC-MS/MS proteomics analysis in the MLIV mouse model and reconstituted molecular signatures of the disease in either freshly isolated populations of neurons, astrocytes, oligodendrocytes, and neural stem cells, or whole tissue cortical homogenates from young adult symptomatic Mcoln1-/- mice. Our analysis confirmed on the molecular level major histopathological hallmarks of MLIV universally present in Mcoln1-/- tissue and brain cells, such as hypomyelination, lysosomal dysregulation, and impaired metabolism of lipids and polysaccharides. Importantly, pathway analysis in brain cells revealed mitochondria-related alterations in all Mcoln1-/- brain cells, except oligodendrocytes, that was not possible to resolve in whole tissue. We also report unique proteome signatures and dysregulated pathways for each brain cell population used in this study. These data shed new light on cell-intrinsic mechanisms of MLIV and provide new insights for biomarker discovery and validation to advance translational studies for this disease.

Keywords:  TRPML1; biomarkers; brain cells; cell specific proteomics; central nervous system; lysosomal disease; mucolipidosis

DOI:  https://doi.org/10.3389/fnmol.2023.1215425
Brain Commun. 2023 ;5(4): fcad216

Association of the fibronectin type III domain-containing protein 5 rs1746661 single nucleotide polymorphism with reduced brain glucose metabolism in elderly humans.

Alzheimer’s Disease Neuroimaging Initiative

  Fibronectin type III domain-containing protein 5 (FNDC5) and its derived hormone, irisin, have been associated with metabolic control in humans, with described FNDC5 single nucleotide polymorphisms being linked to obesity and metabolic syndrome. Decreased brain FNDC5/irisin has been reported in subjects with dementia due to Alzheimer's disease. Since impaired brain glucose metabolism develops in ageing and is prominent in Alzheimer's disease, here, we examined associations of a single nucleotide polymorphism in the FNDC5 gene (rs1746661) with brain glucose metabolism and amyloid-β deposition in a cohort of 240 cognitively unimpaired and 485 cognitively impaired elderly individuals from the Alzheimer's Disease Neuroimaging Initiative. In cognitively unimpaired elderly individuals harbouring the FNDC5 rs1746661(T) allele, we observed a regional reduction in low glucose metabolism in memory-linked brain regions and increased brain amyloid-β PET load. No differences in cognition or levels of cerebrospinal fluid amyloid-β42, phosphorylated tau and total tau were observed between FNDC5 rs1746661(T) allele carriers and non-carriers. Our results indicate that a genetic variant of FNDC5 is associated with low brain glucose metabolism in elderly individuals and suggest that FNDC5 may participate in the regulation of brain metabolism in brain regions vulnerable to Alzheimer's disease pathophysiology. Understanding the associations between genetic variants in metabolism-linked genes and metabolic brain signatures may contribute to elucidating genetic modulators of brain metabolism in humans.

Keywords:  Alzheimer’s disease; FNDC5/irisin; PET-FDG; glucose metabolism; single nucleotide polymorphism

DOI:  https://doi.org/10.1093/braincomms/fcad216
Adv Neurobiol. 2023 ;33 357-397

Lipids and Secretory Vesicle Exocytosis.

Isaac O Akefe, Shona L Osborne, Benjamin Matthews, Tristan P Wallis, Frédéric A Meunier.

  In recent years, the number of studies implicating lipids in the regulation of synaptic vesicle exocytosis has risen considerably. It has become increasingly clear that lipids such as phosphoinositides, lysophospholipids, cholesterol, arachidonic acid and myristic acid play critical regulatory roles in the processes leading up to exocytosis. Lipids may affect membrane fusion reactions by altering the physical properties of the membrane, recruiting key regulatory proteins, concentrating proteins into exocytic "hotspots" or by modulating protein functions allosterically. Discrete changes in phosphoinositides concentration are involved in multiple trafficking events including exocytosis and endocytosis. Lipid-modifying enzymes such as the DDHD2 isoform of phospholipase A1 were recently shown to contribute to memory acquisition via dynamic modifications of the brain lipid landscape. Considering the increasing reports on neurodegenerative disorders associated with aberrant intracellular trafficking, an improved understanding of the control of lipid pathways is physiologically and clinically significant and will afford unique insights into mechanisms and therapeutic methods for neurodegenerative diseases. Consequently, this chapter will discuss the different classes of lipids, phospholipase enzymes, the evidence linking them to synaptic neurotransmitter release and how they act to regulate key steps in the multi-step process leading to neuronal communication and memory acquisition.

Keywords:  Cholesterol; Exocytosis; Fatty acids; Lipid post-translational modification; Neurotransmission; Phosphoinositide; Phospholipases; Phospholipids; Secretory vesicle; Sphingolipids

DOI:  https://doi.org/10.1007/978-3-031-34229-5_14
Aging Cell. 2023 Aug 23. e13911

Accelerated aging in mice with astrocytic redox imbalance as a consequence of SOD2 deletion.

Konstantinos Tsesmelis, Gandhari Maity-Kumar, Dana Croner, Jasmin Sprissler, Miltiadis Tsesmelis, Tabea Hein, Bernd Baumann, Thomas Wirth.

  Aging of the central nervous system (CNS) leads to motoric and cognitive decline and increases the probability for neurodegenerative disease development. Astrocytes fulfill central homeostatic functions in the CNS including regulation of immune responses and metabolic support of neurons and oligodendrocytes. In this study, we investigated the effect of redox imbalance in astrocytes by using a conditional astrocyte-specific SOD2-deficient mouse model (SOD2ako ) and analyzed these animals at different stages of their life. SOD2ako mice did not exhibit any overt phenotype within the first postnatal weeks. However, already as young adults, they displayed progressive motoric impairments. Moreover, as these mice grew older, they exhibited signs of a progeroid phenotype and early death. Histological analysis in moribund SOD2ako mice revealed the presence of age-related brain alterations, neuroinflammation, neuronal damage and myelin impairment in brain and spinal cord. Additionally, transcriptome analysis of primary astrocytes revealed that SOD2 deletion triggered a hypometabolic state and promoted polarization toward A1-neurotoxic status, possibly underlying the neuronal and myelin deficits. Conclusively, our study identifies maintenance of ROS homeostasis in astrocytes as a critical prerequisite for physiological CNS aging.

Keywords:  CNS; SOD2; aging; astrocytes; brain; motoric impairment; oxidative stress; premature aging

DOI:  https://doi.org/10.1111/acel.13911
Biomolecules. 2023 Aug 07. pii: 1225. [Epub ahead of print]13(8):

Mechanisms of Modulation of Mitochondrial Architecture.

Juan Pablo Muñoz, Fernanda Luisa Basei, María Laura Rojas, David Galvis, Antonio Zorzano.

  Mitochondrial network architecture plays a critical role in cellular physiology. Indeed, alterations in the shape of mitochondria upon exposure to cellular stress can cause the dysfunction of these organelles. In this scenario, mitochondrial dynamics proteins and the phospholipid composition of the mitochondrial membrane are key for fine-tuning the modulation of mitochondrial architecture. In addition, several factors including post-translational modifications such as the phosphorylation, acetylation, SUMOylation, and o-GlcNAcylation of mitochondrial dynamics proteins contribute to shaping the plasticity of this architecture. In this regard, several studies have evidenced that, upon metabolic stress, mitochondrial dynamics proteins are post-translationally modified, leading to the alteration of mitochondrial architecture. Interestingly, several proteins that sustain the mitochondrial lipid composition also modulate mitochondrial morphology and organelle communication. In this context, pharmacological studies have revealed that the modulation of mitochondrial shape and function emerges as a potential therapeutic strategy for metabolic diseases. Here, we review the factors that modulate mitochondrial architecture.

Keywords:  lipids; membrane contact sites (MCSs); metabolic disease; metabolism; mitochondria; mitochondrial dynamics; pharmacology; post-translational modification; tethers

DOI:  https://doi.org/10.3390/biom13081225
Mol Neurobiol. 2023 Aug 24.

Pyruvate Dehydrogenase-Dependent Metabolic Programming Affects the Oligodendrocyte Maturation and Remyelination.

M Sajad, Insha Zahoor, Faraz Rashid, Mirela Cerghet, Ramandeep Rattan, Shailendra Giri.

  The metabolic needs of the premature/premyelinating oligodendrocytes (pre-OLs) and mature oligodendrocytes (OLs) are distinct. The metabolic control of oligodendrocyte maturation from the pre-OLs to the OLs is not fully understood. Here, we show that the terminal maturation and higher mitochondrial respiration in the OLs is an integrated process controlled through pyruvate dehydrogenase complex (Pdh). Combined bioenergetics and metabolic studies show that OLs show elevated mitochondrial respiration than the pre-OLs. Our signaling studies show that the increased mitochondrial respiration activity in the OLs is mediated by the activation of Pdh due to inhibition of the pyruvate dehydrogenase kinase-1 (Pdhk1) that phosphorylates and inhibits Pdh activity. Accordingly, when Pdhk1 is directly expressed in the pre-OLs, they fail to mature into the OLs. While Pdh converts pyruvate into the acetyl-CoA by its oxidative decarboxylation, our study shows that Pdh-dependent acetyl-CoA generation from pyruvate contributes to the acetylation of the bHLH family transcription factor, oligodendrocyte transcription factor 1 (Olig1) which is known to be involved in the OL maturation. Pdh inhibition via direct expression of Pdhk1 in the pre-OLs blocks the Olig1-acetylation and OL maturation. Using the cuprizone model of demyelination, we show that Pdh is deactivated during the demyelination phase, which is however reversed in the remyelination phase upon cuprizone withdrawal. In addition, Pdh activity status correlates with the Olig1-acetylation status in the cuprizone model. Hence, the Pdh metabolic node activation allows a robust mitochondrial respiration and activation of a molecular program necessary for the terminal maturation of oligodendrocytes. Our findings open a new dialogue in the developmental biology that links cellular development and metabolism. These findings have far-reaching implications in the development of therapies for a variety of demyelinating disorders including multiple sclerosis.

Keywords:  Metabolism; Multiple sclerosis; OPC maturation; Oligodendrocytes; Pdh; Pdhk1

DOI:  https://doi.org/10.1007/s12035-023-03546-x
Brain Sci. 2023 Aug 04. pii: 1166. [Epub ahead of print]13(8):

Lipid Metabolism Disorder in Cerebrospinal Fluid Related to Parkinson's Disease.

Jiewen Qiu, Lijian Wei, Yilin Su, Yuting Tang, Guoyou Peng, Yimin Hu, Yan He, Hanqun Liu, Wenyuan Guo, Zhuohu Wu, Pingyi Xu, Mingshu Mo.

   BACKGROUND: Abnormal accumulation of lipids is found in dopamine neurons and resident microglia in the substantia nigra of patients with Parkinson's disease (PD). The accumulation of lipids is an important risk factor for PD. Previous studies have mainly focussed on lipid metabolism in peripheral blood, but little attention has been given to cerebrospinal fluid (CSF). We drew the lipidomic signature in CSF from PD patients and evaluated the role of lipids in CSF as biomarkers for PD diagnosis.
METHODS: Based on lipidomic approaches, we investigated and compared lipid metabolism in CSF from PD patients and healthy controls without dyslipidaemia in peripheral blood and explored the relationship of lipids between CSF and serum by Pearson correlation analysis.
RESULTS: A total of 231 lipid species were detected and classified into 13 families in the CSF. The lipid families, including phosphatidylcholine (PC), sphingomyelin (SM) and cholesterol ester (CE), had significantly increased expression compared with the control. Hierarchical clustering was performed to distinguish PD patients based on the significantly changed expression of 34 lipid species. Unsupervised and supervised methods were used to refine this classification. A total of 12 lipid species, including 3-hydroxy-dodecanoyl-carnitine, Cer(d18:1/24:1), CE(20:4), CE(22:6), PC(14:0/18:2), PC(O-18:3/20:2), PC(O-20:2/24:3), SM(d18:0/16:0), SM(d18:2/14:0), SM(d18:2/24:1), SM(d18:1/20:1) and SM(d18:1/12:0), were selected to draw the lipidomic signature of PD. Correlation analysis was performed and showed that the CE family and CE (22:6) in CSF had a positive association with total cholesterol in the peripheral blood from PD patients but not from healthy controls.
CONCLUSIONS: Our results revealed that the lipidomic signature in CSF may be considered a potential biomarker for PD diagnosis, and increased CE, PC and SM in CSF may reveal pathological changes in PD patients, such as blood-brain barrier leakage.

Keywords:  Parkinson’s disease; biomarker; cerebrospinal fluid; lipid metabolism

DOI:  https://doi.org/10.3390/brainsci13081166
Metabolites. 2023 Jul 26. pii: 885. [Epub ahead of print]13(8):

The Impacts of Slc19a3 Deletion and Intestinal SLC19A3 Insertion on Thiamine Distribution and Brain Metabolism in the Mouse.

Anita Wen, Ying Zhu, Sook Wah Yee, Brian I Park, Kathleen M Giacomini, Andrew S Greenberg, John W Newman.

  The Thiamine Transporter 2 (THTR2) encoded by SLC19A3 plays an ill-defined role in the maintenance of tissue thiamine, thiamine monophosphate, and thiamine diphosphate (TDP) levels. To evaluate the impact of THTR2 on tissue thiamine status and metabolism, we expressed the human SLC19A3 transgene in the intestine of total body Slc19a3 knockout (KO) mice. Male and female wildtype (WT) and transgenic (TG) mice were fed either 17 mg/kg (1×) or 85 mg/kg (5×) thiamine hydrochloride diet, while KOs were only fed the 5× diet. Thiamine vitamers in plasma, red blood cells, duodenum, brain, liver, kidney, heart, and adipose tissue were measured. Untargeted metabolomics were performed on the brain tissues of groups with equivalent plasma thiamine. KO mice had ~two- and ~three-fold lower plasma and brain thiamine levels than WT on the 5× diet. Circulating vitamers were sensitive to diet and equivalent in TG and WT mice. However, TG had 60% lower thiamine but normal brain TDP levels regardless of diet, with subtle differences in the heart and liver. The loss of THTR2 reduced levels of nucleic acid and amino acid derivatives in the brain. Therefore, mutation or inhibition of THTR2 may alter the brain metabolome and reduce the thiamine reservoir for TDP biosynthesis.

Keywords:  THTR2; brain metabolism; metabolomics; thiamine; thiamine transporter 2

DOI:  https://doi.org/10.3390/metabo13080885
Aging Cell. 2023 Aug 23. e13954

Alterations of lipid-mediated mitophagy result in aging-dependent sensorimotor defects.

Natalia Oleinik, Onder Albayram, Mohamed Faisal Kassir, F Cansu Atilgan, Chase Walton, Eda Karakaya, John Kurtz, Alexander Alekseyenko, Habeeb Alsudani, Megan Sheridan, Zdzislaw M Szulc, Besim Ogretmen.

  The metabolic consequences of mitophagy alterations due to age-related stress in healthy aging brains versus neurodegeneration remain unknown. Here, we demonstrate that ceramide synthase 1 (CerS1) is transported to the outer mitochondrial membrane by the p17/PERMIT transporter that recognizes mislocalized mitochondrial ribosomes (mitoribosomes) via 39-FLRN-42 residues, inducing ceramide-mediated mitophagy. P17/PERMIT-CerS1-mediated mitophagy attenuated the argininosuccinate/fumarate/malate axis and induced d-glucose and fructose accumulation in neurons in culture and brain tissues (primarily in the cerebellum) of wild-type mice in vivo. These metabolic changes in response to sodium-selenite were nullified in the cerebellum of CerS1to/to (catalytically inactive for C18-ceramide production CerS1 mutant), PARKIN-/- or p17/PERMIT-/- mice that have dysfunctional mitophagy. Whereas sodium selenite induced mitophagy in the cerebellum and improved motor-neuron deficits in aged wild-type mice, exogenous fumarate or malate prevented mitophagy. Attenuating ceramide-mediated mitophagy enhanced damaged mitochondria accumulation and age-dependent sensorimotor abnormalities in p17/PERMIT-/- mice. Reinstituting mitophagy using a ceramide analog drug with selenium conjugate, LCL768, restored mitophagy and reduced malate/fumarate metabolism, improving sensorimotor deficits in old p17/PERMIT-/- mice. Thus, these data describe the metabolic consequences of alterations to p17/PERMIT/ceramide-mediated mitophagy associated with the loss of mitochondrial quality control in neurons and provide therapeutic options to overcome age-dependent sensorimotor deficits and related disorders like amyotrophic lateral sclerosis (ALS).

Keywords:  CerS1; Drp1; aging; ceramide; mitochondrial metabolism; mitophagy; neurodegeneration; sensorimotor defects

DOI:  https://doi.org/10.1111/acel.13954
Nutrients. 2023 Aug 15. pii: 3581. [Epub ahead of print]15(16):

Postnatal Overfeeding in Rodents Induces a Neurodevelopment Delay and Anxious-like Behaviour Accompanied by Sex- and Brain-Region-Specific Synaptic and Metabolic Changes.

Andreia Amaro, Diana Sousa, Mariana Sá-Rocha, Marcos Divino Ferreira-Junior, Daniela Rosendo-Silva, Lucas Paulo Jacinto Saavedra, Cátia Barra, Tamaeh Monteiro-Alfredo, Rodrigo Mello Gomes, Paulo Cezar de Freitas Mathias, Filipa I Baptista, Paulo Matafome.

  Nutritional disturbances during the early postnatal period can have long-lasting effects on neurodevelopment and may be related to behavioural changes at adulthood. While such neuronal connection disruption can contribute to social and behaviour alterations, the dysregulation of the neuroendocrine pathways involved in nutrient-sensing balance may also cause such impairments, although the underlying mechanisms are still unclear. We aimed to evaluate sex-specific neurodevelopmental and behavioural changes upon postnatal overfeeding and determine the potential underpinning mechanisms at the central nervous system level, with a focus on the interconnection between synaptic and neuroendocrine molecular alterations. At postnatal day 3 (PND3) litters were culled to three animals (small litter procedure). Neurodevelopmental tests were conducted at infancy, whereas behavioural tests to assess locomotion, anxiety, and memory were performed at adolescence, together with molecular analysis of the hippocampus, hypothalamus, and prefrontal cortex. At infancy, females presented impaired acquisition of an auditory response, eye opening, olfactory discrimination, and vestibular system development, suggesting that female offspring neurodevelopment/maturation was deeply affected. Male offspring presented a transitory delay in locomotor performance., while both offspring had lower upper limb strength. At adolescence, both sexes presented anxious-like behaviour without alterations in short-term memory retention. Both males and females presented lower NPY1R levels in a region-specific manner. Furthermore, both sexes presented synaptic changes in the hippocampus (lower GABAA in females and higher GABAA levels in males), while, in the prefrontal cortex, similar higher GABAA receptor levels were observed. At the hypothalamus, females presented synaptic changes, namely higher vGLUT1 and PSD95 levels. Thus, we demonstrate that postnatal overfeeding modulates offspring behaviour and dysregulates nutrient-sensing mechanisms such as NPY and GABA in a sex- and brain-region-specific manner.

Keywords:  anxious-like behaviour; energy balance; lactation; neurodevelopment; overfeeding; synaptic balance

DOI:  https://doi.org/10.3390/nu15163581
Nutrients. 2023 Aug 11. pii: 3535. [Epub ahead of print]15(16):

Long-Term Treatment of Lipoprotein Lipase Deficiency with Medium-Chain Triglyceride-Enriched Diet: A Case Series.

Liali Aljouda, Laura Nagy, Andreas Schulze.

  Background: Lipoprotein lipase (LPL) deficiency is a genetic condition. Affected individuals typically develop symptoms related to severe and persistent hypertriglyceridemia, such as abdominal pain and recurrent pancreatitis, before 10 years of age. No pharmacological treatment sustainably lowering triglycerides (TGs) in LPL deficiency patients has been proven to be effective. This study investigated whether a long-chain triglyceride (LCT)-restricted, medium-chain triglyceride (MCT)-supplemented diet enables a meaningful reduction in TGs and reduces LPL-related symptoms in children with LPL deficiency. Methods: A single-center retrospective case series study of LPL deficiency patients treated at the Hospital of Sick Children between January 2000 and December 2022 was carried out. Data, extracted from hospital charts, included demographics, diagnosis confirmation, clinical and imaging observations, and biochemical profiles. Results: Seven patients with hypertriglyceridemia > 20 mmol/L suspected of an LPL deficiency diagnosis were included. Six patients had a confirmed molecular diagnosis of LPL deficiency, and one had glycogen storage disease type 1a (GSD1a). Clinical presentation was at a median of 30 days of age (range 1-105), and treatment start, excluding one late-treated patient, was at a median of 42 days (range 2-106). The observation and treatment period of the LPL patients was 48.0 patient years (median 7.1, range 4.3-15.5). The LCT-restricted and MCT-supplemented diet led to an immediate drop in TGs in six out of six LPL patients. TGs improved from a median of 40.9 mmol/L (range 11.4-276.5) pre-treatment to a median of 12.0 mmol/L (range 1.1-36.6) during treatment, total cholesterol from 7.6 mmol/L (4.9-27.0) to 3.9 mmol/L (1.7-8.2), and pancreatic lipase from 631 IU/L (30-1200) to 26.5 IU/L (5-289). In 48 patient years, there was only one complication of pancreatitis and no other disease-specific manifestations or complications. Catch-up growth was observed in one late-treated patient. All patients maintained normal growth and development. As expected, the diet failed to treat hypertriglyceridemia in the GSD1a patient. Conclusions: The dietary restriction of LCT in combination with MCT supplementation as long-term management of pediatric patients with LPL deficiency was feasible, well tolerated, and clinically effective in reducing TG levels and in preventing LPL-related complications.

Keywords:  MCT diet; inborn errors of metabolism; lipoprotein lipase deficiency

DOI:  https://doi.org/10.3390/nu15163535
Pharmaceutics. 2023 Jul 31. pii: 2062. [Epub ahead of print]15(8):

Distribution of Monocarboxylate Transporters in Brain and Choroid Plexus Epithelium.

Masaki Ueno, Yoichi Chiba, Ryuta Murakami, Yumi Miyai, Koichi Matsumoto, Keiji Wakamatsu, Genta Takebayashi, Naoya Uemura, Ken Yanase.

  The choroid plexus (CP) plays central roles in regulating the microenvironment of the central nervous system by secreting the majority of cerebrospinal fluid (CSF) and controlling its composition. A monolayer of epithelial cells of CP plays a significant role in forming the blood-CSF barrier to restrict the movement of substances between the blood and ventricles. CP epithelial cells are equipped with transporters for glucose and lactate that are used as energy sources. There are many review papers on glucose transporters in CP epithelial cells. On the other hand, distribution of monocarboxylate transporters (MCTs) in CP epithelial cells has received less attention compared with glucose transporters. Some MCTs are known to transport lactate, pyruvate, and ketone bodies, whereas others transport thyroid hormones. Since CP epithelial cells have significant carrier functions as well as the barrier function, a decline in the expression and function of these transporters leads to a poor supply of thyroid hormones as well as lactate and can contribute to the process of age-associated brain impairment and pathophysiology of neurodegenerative diseases. In this review paper, recent findings regarding the distribution and significance of MCTs in the brain, especially in CP epithelial cells, are summarized.

Keywords:  choroid plexus; epithelial cell; lactate; monocarboxylate transporter; thyroid hormone

DOI:  https://doi.org/10.3390/pharmaceutics15082062
Proteins. 2023 Aug 24.

Mechanistic understanding of bacterial FAALs and the role of their homologs in eukaryotes.

Sudipta Mondal, Biswajit Pal, Rajan Sankaranarayanan.

  Fatty acids are used in fundamental cellular processes, such as membrane biogenesis, energy generation, post-translational modification of proteins, and so forth. These processes require the activation of fatty acids by adenosine triphosphate (ATP), followed by condensation with coenzyme-A (CoA), catalyzed by the omnipresent enzyme called Fatty acyl-CoA ligases (FACLs). However, Fatty acyl-AMP ligases (FAALs), the structural homologs of FACLs, operate in an unprecedented CoA-independent manner. FAALs transfer fatty acids to the acyl carrier protein (ACP) domain of polyketide synthases (PKS) and non-ribosomal peptide synthetases (NRPS) for the biosynthesis of various antibiotics, lipopeptides, virulent complex lipids, and so forth in bacteria. Recent structural and biochemical insights from our group provide a detailed understanding of the mode of CoA rejection and ACP acceptance by FAALs. In this review, we have discussed advances in the mechanistic, evolutionary, and functional understanding of FAALs and FAAL-like domains across life forms. Here, we are proposing a "Five-tier" mechanistic model to explain the specificity of FAALs. We further demonstrate how FAAL-like domains have been repurposed into a new family of proteins in eukaryotes with a novel function in lipid metabolism.

Keywords:  disco-interacting protein 2; fatty acyl-AMP ligase; fatty acyl-CoA ligase; lipid metabolism; protein evolution

DOI:  https://doi.org/10.1002/prot.26576
Nat Commun. 2023 Aug 25. 14(1): 5197

Microglial REV-ERBα regulates inflammation and lipid droplet formation to drive tauopathy in male mice.

Jiyeon Lee, Julie M Dimitry, Jong Hee Song, Minsoo Son, Patrick W Sheehan, Melvin W King, G Travis Tabor, Young Ah Goo, Mitchell A Lazar, Leonard Petrucelli, Erik S Musiek.

Alzheimer's disease, the most common age-related neurodegenerative disease, is characterized by tau aggregation and associated with disrupted circadian rhythms and dampened clock gene expression. REV-ERBα is a core circadian clock protein which also serves as a nuclear receptor and transcriptional repressor involved in lipid metabolism and macrophage function. Global REV-ERBα deletion has been shown to promote microglial activation and mitigate amyloid plaque formation. However, the cell-autonomous effects of microglial REV-ERBα in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deletion enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. These events impair microglial tau phagocytosis, which can be partially rescued by blockage of LD formation. In vivo, microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in two mouse tauopathy models, specifically in male mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.

DOI: https://doi.org/10.1038/s41467-023-40927-1
Exp Mol Med. 2023 Aug 23.

An integrated view of lipid metabolism in ferroptosis revisited via lipidomic analysis.

Jong Woo Kim, Ji-Yoon Lee, Mihee Oh, Eun-Woo Lee.

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. This process contributes to cellular and tissue damage in various human diseases, such as cardiovascular diseases, neurodegeneration, liver disease, and cancer. Although polyunsaturated fatty acids (PUFAs) in membrane phospholipids are preferentially oxidized, saturated/monounsaturated fatty acids (SFAs/MUFAs) also influence lipid peroxidation and ferroptosis. In this review, we first explain how cells differentially synthesize SFA/MUFAs and PUFAs and how they control fatty acid pools via fatty acid uptake and β-oxidation, impacting ferroptosis. Furthermore, we discuss how fatty acids are stored in different lipids, such as diacyl or ether phospholipids with different head groups; triglycerides; and cholesterols. Moreover, we explain how these fatty acids are released from these molecules. In summary, we provide an integrated view of the diverse and dynamic metabolic processes in the context of ferroptosis by revisiting lipidomic studies. Thus, this review contributes to the development of therapeutic strategies for ferroptosis-related diseases.

DOI: https://doi.org/10.1038/s12276-023-01077-y
Hum Brain Mapp. 2023 Aug 22.

Association between gene expression and functional-metabolic architecture in Parkinson's disease.

Zhenxiang Zang, Xiaolong Zhang, Tianbin Song, Jiping Li, Binbin Nie, Shanshan Mei, Zhi'an Hu, Yuqing Zhang, Jie Lu.

  Gene expression plays a critical role in the pathogenesis of Parkinson's disease (PD). How gene expression profiles are correlated with functional-metabolic architecture remains obscure. We enrolled 34 PD patients and 25 age-and-sex-matched healthy controls for simultaneous 18 F-FDG-PET/functional MRI scanning during resting state. We investigated the functional gradients and the ratio of standard uptake value. Principal component analysis was used to further combine the functional gradients and glucose metabolism into functional-metabolic architecture. Using partial least squares (PLS) regression, we introduced the transcriptomic data from the Allen Institute of Brain Sciences to identify gene expression patterns underlying the affected functional-metabolic architecture in PD. Between-group comparisons revealed significantly higher gradient variation in the visual, somatomotor, dorsal attention, frontoparietal, default mode, and subcortical network (pFDR < .048) in PD. Increased FDG-uptake was found in the somatomotor and ventral attention network while decreased FDG-uptake was found in the visual network (pFDR < .008). Spatial correlation analysis showed consistently affected patterns of functional gradients and metabolism (p = 2.47 × 10-8 ). PLS analysis and gene ontological analyses further revealed that genes were mainly enriched for metabolic, catabolic, cellular response to ions, and regulation of DNA transcription and RNA biosynthesis. In conclusion, our study provided genetic pathological mechanism to explain imaging-defined brain functional-metabolic architecture of PD.

Keywords:  Parkinson's disease; gene expression; glucose metabolism; gradients; hybrid PET/MRI

DOI:  https://doi.org/10.1002/hbm.26443
Aging Dis. 2023 Aug 21.

Glycometabolic Reprogramming of Microglia in Neurodegenerative Diseases: Insights from Neuroinflammation.

Qi Huang, Yanfu Wang, Shanshan Chen, Fengxia Liang.

Neurodegenerative diseases (ND) are conditions defined by progressive deterioration of the structure and function of the nervous system. Some major examples include Alzheimer's disease (AD), Parkinson's disease (PD), and Amyotrophic lateral sclerosis (ALS). These diseases lead to various dysfunctions, like impaired cognition, memory, and movement. Chronic neuroinflammation may underlie numerous neurodegenerative disorders. Microglia, an important immunocell in the brain, plays a vital role in defending against neuroinflammation. When exposed to different stimuli, microglia are activated and assume different phenotypes, participating in immune regulation of the nervous system and maintaining tissue homeostasis. The immunological activity of activated microglia is affected by glucose metabolic alterations. However, in the context of chronic neuroinflammation, specific alterations of microglial glucose metabolism and their mechanisms of action remain unclear. Thus, in this paper, we review the glycometabolic reprogramming of microglia in ND. The key molecular targets and main metabolic pathways are the focus of this research. Additionally, this study explores the mechanisms underlying microglial glucose metabolism reprogramming in ND and offers an analysis of the most recent therapeutic advancements. The ultimate aim is to provide insights into the development of potential treatments for ND.

DOI: https://doi.org/10.14336/AD.2023.0807
Neurobiol Dis. 2023 Aug 22. pii: S0969-9961(23)00284-X. [Epub ahead of print] 106269

Mitochondrial dysfunction underlies impaired neurovascular coupling following traumatic brain injury.

Gerben van Hameren, Jamil Muradov, Anna Minarik, Refat Aboghazleh, Sophie Orr, Shayna Cort, Keiran Andrews, Caitlin McKenna, Nga Thy Pham, Mark A MacLean, Alon Friedman.

  Traumatic brain injury (TBI) involves an acute injury (primary damage), which may evolve in the hours to days after impact (secondary damage). Seizures and cortical spreading depolarization (CSD) are metabolically demanding processes that may worsen secondary brain injury. Metabolic stress has been associated with mitochondrial dysfunction, including impaired calcium homeostasis, reduced ATP production, and elevated ROS production. However, the association between mitochondrial impairment and vascular function after TBI is poorly understood. Here, we explored this association using a rodent closed head injury model. CSD is associated with neurobehavioral decline after TBI. Craniotomy was performed to elicit CSD via electrical stimulation or to induce seizures via 4-aminopyridine application. We measured vascular dysfunction following CSDs and seizures in TBI animals using laser doppler flowmetry. We observed a more profound reduction in local cortical blood flow in TBI animals compared to healthy controls. CSD resulted in mitochondrial dysfunction and pathological signs of increased oxidative stress adjacent to the vasculature. We explored these findings further using electron microscopy and found that TBI and CSDs resulted in vascular morphological changes and mitochondrial cristae damage in astrocytes, pericytes and endothelial cells. Overall, we provide evidence that CSDs induce mitochondrial dysfunction, impaired cortical blood flow, and neurobehavioral deficits in the setting of TBI.

Keywords:  Cortical spreading depolarization; Electrocorticography; In vivo microscopy; Mitochondria; Neurovascular coupling; Reactive oxygen species; Seizures; Traumatic brain injury; electron microscopy

DOI:  https://doi.org/10.1016/j.nbd.2023.106269
Metabolites. 2023 Aug 09. pii: 932. [Epub ahead of print]13(8):

Comparative Metabolomics in Single Ventricle Patients after Fontan Palliation: A Strong Case for a Targeted Metabolic Therapy.

David Renaud, Sabine Scholl-Bürgi, Daniela Karall, Miriam Michel.

  Most studies on single ventricle (SV) circulation take a physiological or anatomical approach. Although there is a tight coupling between cardiac contractility and metabolism, the metabolic perspective on this patient population is very recent. Early findings point to major metabolic disturbances, with both impaired glucose and fatty acid oxidation in the cardiomyocytes. Additionally, Fontan patients have systemic metabolic derangements such as abnormal glucose metabolism and hypocholesterolemia. Our literature review compares the metabolism of patients with a SV circulation after Fontan palliation with that of patients with a healthy biventricular (BV) heart, or different subtypes of a failing BV heart, by Pubmed review of the literature on cardiac metabolism, Fontan failure, heart failure (HF), ketosis, metabolism published in English from 1939 to 2023. Early evidence demonstrates that SV circulation is not only a hemodynamic burden requiring staged palliation, but also a metabolic issue with alterations similar to what is known for HF in a BV circulation. Alterations of fatty acid and glucose oxidation were found, resulting in metabolic instability and impaired energy production. As reported for patients with BV HF, stimulating ketone oxidation may be an effective treatment strategy for HF in these patients. Few but promising clinical trials have been conducted thus far to evaluate therapeutic ketosis with HF using a variety of instruments, including ketogenic diet, ketone esters, and sodium-glucose co-transporter-2 (SGLT2) inhibitors. An initial trial on a small cohort demonstrated favorable outcomes for Fontan patients treated with SGLT2 inhibitors. Therapeutic ketosis is worth considering in the treatment of Fontan patients, as ketones positively affect not only the myocardial energy metabolism, but also the global Fontan physiopathology. Induced ketosis seems promising as a concerted therapeutic strategy.

Keywords:  Fontan; biventricular; heart failure; ketogenic therapy; ketones; metabolism; nutrition; single ventricle

DOI:  https://doi.org/10.3390/metabo13080932
Acta Neuropathol Commun. 2023 Aug 21. 11(1): 135

Inhibition of acid sphingomyelinase reduces reactive astrocyte secretion of mitotoxic extracellular vesicles and improves Alzheimer's disease pathology in the 5xFAD mouse.

Simone M Crivelli, Zainuddin Quadri, Hemendra J Vekaria, Zhihui Zhu, Priyanka Tripathi, Ahmed Elsherbini, Liping Zhang, Patrick G Sullivan, Erhard Bieberich.

  In Alzheimer's disease (AD), reactive astrocytes produce extracellular vesicles (EVs) that affect mitochondria in neurons. Here, we show that Aβ-induced generation of the sphingolipid ceramide by acid sphingomyelinase (A-SMase) triggered proinflammatory cytokine (C1q, TNF-α, IL-1α) release by microglia, which induced the reactive astrocytes phenotype and secretion of EVs enriched with ceramide. These EVs impeded the capacity of neurons to respond to energy demand. Inhibition of A-SMase with Arc39 and Imipramine reduced the secretion of cytokines from microglia, prompting us to test the effect of Imipramine on EV secretion and AD pathology in the 5xFAD mouse model. Brain derived-EVs from 5xFAD mice treated with Imipramine contained reduced levels of the astrocytic marker GFAP, ceramide, and Aβ and did not impair mitochondrial respiration when compared to EVs derived from untreated 5xFAD brain. Consistently, Imipramine-treated 5xFAD mice showed reduced AD pathology. Our study identifies A-SMase inhibitors as potential AD therapy by preventing cyotokine-elicited secretion of mitotoxic EVs from astrocytes.

Keywords:  5xFAD; Acid sphingomyelinase; Astrocytes; C1q; Extracellular vesicle; IL-1α; Imipramine; Microglia; Mitochondria; TNF-α

DOI:  https://doi.org/10.1186/s40478-023-01633-7
Prostaglandins Other Lipid Mediat. 2023 Aug 23. pii: S1098-8823(23)00066-7. [Epub ahead of print] 106769

A Novel HSPB1S139F Mouse Model of Charcot-Marie-Tooth Disease.

Keila S Espinoza, Kyra N Hermanson, Cameron A Beard, Nicholas U Schwartz, Justin M Snider, Benjamin E Low, Michael V Wiles, Yusuf A Hannun, Lina M Obeid, Ashley J Snider.

  Charcot-Marie-Tooth Disease (CMT) is a commonly inherited peripheral polyneuropathy. Clinical manifestations for this disease include symmetrical distal polyneuropathy, altered deep tendon reflexes, distal sensory loss, foot deformities, and gait abnormalities. Genetic mutations in heat shock proteins have been linked to CMT2. Specifically, mutations in the heat shock protein B1 (HSPB1) gene encoding for heat shock protein 27 (Hsp27) have been linked to CMT2F and distal hereditary motor and sensory neuropathy type 2B (dHMSN2B) subtype. The goal of the study was to examine the role of an endogenous mutation in HSPB1 in vivo and to define the effects of this mutation on motor function and pathology in a novel animal model. As sphingolipids have been implicated in hereditary and sensory neuropathies, we examined sphingolipid metabolism in central and peripheral nervous tissues in 3-month-old HspS139F mice. Though sphingolipid levels were not altered in sciatic nerves from HspS139F mice, ceramides and deoxyceramides, as well as sphingomyelins (SMs) were elevated in brain tissues from HspS139F mice. Histology was utilized to further characterize HspS139F mice. HspS139F mice exhibited no alterations to the expression and phosphorylation of neurofilaments, or in the expression of acetylated α-tubulin in the brain or sciatic nerve. Interestingly, HspS139F mice demonstrated cerebellar demyelination. Locomotor function, grip strength and gait were examined to define the role of HspS139F in the clinical phenotypes associated with CMT2F. Gait analysis revealed no differences between HspWT and HspS139F mice. However, both coordination and grip strength were decreased in 3-month-old HspS139F mice. Together these data suggest that the endogenous S139F mutation in HSPB1 may serve as a mouse model for hereditary and sensory neuropathies such as CMT2F.

Keywords:  Charcot-Marie-Tooth 2F (CMT2F); acetylated α-tubulin; ceramide synthase (CerS); hereditary sensory and autonomic neuropathy type 1 (HSAN1); phospho-neurofilament

DOI:  https://doi.org/10.1016/j.prostaglandins.2023.106769
Nat Commun. 2023 Aug 22. 14(1): 5114

Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming.

Erika M Palmieri, Ronald Holewinski, Christopher L McGinity, Ciro L Pierri, Nunziata Maio, Jonathan M Weiss, Vincenzo Tragni, Katrina M Miranda, Tracey A Rouault, Thorkell Andresson, David A Wink, Daniel W McVicar.

M1 macrophages enter a glycolytic state when endogenous nitric oxide (NO) reprograms mitochondrial metabolism by limiting aconitase 2 and pyruvate dehydrogenase (PDH) activity. Here, we provide evidence that NO targets the PDH complex by using lipoate to generate nitroxyl (HNO). PDH E2-associated lipoate is modified in NO-rich macrophages while the PDH E3 enzyme, also known as dihydrolipoamide dehydrogenase (DLD), is irreversibly inhibited. Mechanistically, we show that lipoate facilitates NO-mediated production of HNO, which interacts with thiols forming irreversible modifications including sulfinamide. In addition, we reveal a macrophage signature of proteins with reduction-resistant modifications, including in DLD, and identify potential HNO targets. Consistently, DLD enzyme is modified in an HNO-dependent manner at Cys477 and Cys484, and molecular modeling and mutagenesis show these modifications impair the formation of DLD homodimers. In conclusion, our work demonstrates that HNO is produced physiologically. Moreover, the production of HNO is dependent on the lipoate-rich PDH complex facilitating irreversible modifications that are critical to NO-dependent metabolic rewiring.

DOI: https://doi.org/10.1038/s41467-023-40738-4
Nat Metab. 2023 Aug;5(8): 1275-1289

The pentose phosphate pathway in health and disease.

Tara TeSlaa, Markus Ralser, Jing Fan, Joshua D Rabinowitz.

The pentose phosphate pathway (PPP) is a glucose-oxidizing pathway that runs in parallel to upper glycolysis to produce ribose 5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH). Ribose 5-phosphate is used for nucleotide synthesis, while NADPH is involved in redox homoeostasis as well as in promoting biosynthetic processes, such as the synthesis of tetrahydrofolate, deoxyribonucleotides, proline, fatty acids and cholesterol. Through NADPH, the PPP plays a critical role in suppressing oxidative stress, including in certain cancers, in which PPP inhibition may be therapeutically useful. Conversely, PPP-derived NADPH also supports purposeful cellular generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) for signalling and pathogen killing. Genetic deficiencies in the PPP occur relatively commonly in the committed pathway enzyme glucose-6-phosphate dehydrogenase (G6PD). G6PD deficiency typically manifests as haemolytic anaemia due to red cell oxidative damage but, in severe cases, also results in infections due to lack of leucocyte oxidative burst, highlighting the dual redox roles of the pathway in free radical production and detoxification. This Review discusses the PPP in mammals, covering its roles in biochemistry, physiology and disease.

DOI: https://doi.org/10.1038/s42255-023-00863-2
Front Cell Neurosci. 2023 ;17 1228968

Ferroptosis and mitochondrial dysfunction in acute central nervous system injury.

Wenxue Dong, Fanghe Gong, Yu Zhao, Hongmin Bai, Ruixin Yang.

  Acute central nervous system injuries (ACNSI), encompassing traumatic brain injury (TBI), non-traumatic brain injury like stroke and encephalomeningitis, as well as spinal cord injuries, are linked to significant rates of disability and mortality globally. Nevertheless, effective and feasible treatment plans are still to be formulated. There are primary and secondary injuries occurred after ACNSI. Most ACNSIs exhibit comparable secondary injuries, which offer numerous potential therapeutic targets for enhancing clinical outcomes. Ferroptosis, a newly discovered form of cell death, is characterized as a lipid peroxidation process that is dependent on iron and oxidative conditions, which is also indispensable to mitochondria. Ferroptosis play a vital role in many neuropathological pathways, and ACNSIs may induce mitochondrial dysfunction, thereby indicating the essentiality of the mitochondrial connection to ferroptosis in ACNSIs. Nevertheless, there remains a lack of clarity regarding the involvement of mitochondria in the occurrence of ferroptosis as a secondary injuries of ACNSIs. In recent studies, anti-ferroptosis agents such as the ferroptosis inhibitor Ferrostain-1 and iron chelation therapy have shown potential in ameliorating the deleterious effects of ferroptosis in cases of traumatic ACNSI. The importance of this evidence is extremely significant in relation to the research and control of ACNSIs. Therefore, our review aims to provide researchers focusing on enhancing the therapeutic outcomes of ACNSIs with valuable insights by summarizing the physiopathological mechanisms of ACNSIs and exploring the correlation between ferroptosis, mitochondrial dysfunction, and ACNSIs.

Keywords:  acute central nervous system injury; ferroptosis; mitochondrial homeostasis; spinal cord injury; traumatic brain injury

DOI:  https://doi.org/10.3389/fncel.2023.1228968