bims-medebr 2023-10-01 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2023‒10‒01
fifteen papers selected by
Regina F. Fernández, Johns Hopkins University

The Role of Acyl-CoA β-Oxidation in Brain Metabolism and Neurodegenerative Diseases.
Lactate: A Theranostic Biomarker for Metabolic Psychiatry?
ABCD1 Transporter Deficiency Results in Altered Cholesterol Homeostasis.
Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury.
Characterizing Sex Differences in Mitochondrial Dysfunction After Severe Traumatic Brain Injury in Mice.
Inhibition of fatty acid binding protein-5 in the basolateral amygdala induces anxiolytic effects and accelerates fear memory extinction.
Aspartic Acid in Health and Disease.
The lipid basis of cell death and autophagy.
BACE1 and SCD1 are associated with neurodegeneration.
Pharmacological rescue of mitochondrial and neuronal defects in SPG7 hereditary spastic paraplegia patient neurons using high throughput assays.
d-Amino acids: new clinical pathways for brain diseases.
Metabolic and cell cycle shift induced by the deletion of Dnm1l attenuates the dissolution of pluripotency in mouse embryonic stem cells.
The role of lipid scramblases in regulating lipid distributions at cellular membranes.
Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options.
Porcine Astrocytes and Their Relevance for Translational Neurotrauma Research.

Int J Mol Sci. 2023 Sep 12. pii: 13977. [Epub ahead of print]24(18):

The Role of Acyl-CoA β-Oxidation in Brain Metabolism and Neurodegenerative Diseases.

Sylwia Szrok-Jurga, Jacek Turyn, Areta Hebanowska, Julian Swierczynski, Aleksandra Czumaj, Tomasz Sledzinski, Ewa Stelmanska.

  This review highlights the complex role of fatty acid β-oxidation in brain metabolism. It demonstrates the fundamental importance of fatty acid degradation as a fuel in energy balance and as an essential component in lipid homeostasis, brain aging, and neurodegenerative disorders.

Keywords:  aging; beta-oxidation; brain; fatty acid metabolism; neurodegenerative diseases

DOI:  https://doi.org/10.3390/ijms241813977
Antioxidants (Basel). 2023 Aug 22. pii: 1656. [Epub ahead of print]12(9):

Lactate: A Theranostic Biomarker for Metabolic Psychiatry?

Edward Caddye, Julien Pineau, Joshua Reyniers, Itamar Ronen, Alessandro Colasanti.

  Alterations in neurometabolism and mitochondria are implicated in the pathophysiology of psychiatric conditions such as mood disorders and schizophrenia. Thus, developing objective biomarkers related to brain mitochondrial function is crucial for the development of interventions, such as central nervous system penetrating agents that target brain health. Lactate, a major circulatory fuel source that can be produced and utilized by the brain and body, is presented as a theranostic biomarker for neurometabolic dysfunction in psychiatric conditions. This concept is based on three key properties of lactate that make it an intriguing metabolic intermediate with implications for this field: Firstly, the lactate response to various stimuli, including physiological or psychological stress, represents a quantifiable and dynamic marker that reflects metabolic and mitochondrial health. Second, lactate concentration in the brain is tightly regulated according to the sleep-wake cycle, the dysregulation of which is implicated in both metabolic and mood disorders. Third, lactate universally integrates arousal behaviours, pH, cellular metabolism, redox states, oxidative stress, and inflammation, and can signal and encode this information via intra- and extracellular pathways in the brain. In this review, we expand on the above properties of lactate and discuss the methodological developments and rationale for the use of functional magnetic resonance spectroscopy for in vivo monitoring of brain lactate. We conclude that accurate and dynamic assessment of brain lactate responses might contribute to the development of novel and personalized therapies that improve mitochondrial health in psychiatric disorders and other conditions associated with neurometabolic dysfunction.

Keywords:  brain; imaging; lactate; metabolic psychiatry; mitochondria; neurometabolism; redox

DOI:  https://doi.org/10.3390/antiox12091656
Biomolecules. 2023 Aug 31. pii: 1333. [Epub ahead of print]13(9):

ABCD1 Transporter Deficiency Results in Altered Cholesterol Homeostasis.

Agnieszka Buda, Sonja Forss-Petter, Rong Hua, Yorrick Jaspers, Mark Lassnig, Petra Waidhofer-Söllner, Stephan Kemp, Peter Kim, Isabelle Weinhofer, Johannes Berger.

  X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disorder, is caused by mutations in the peroxisomal transporter ABCD1, resulting in the accumulation of very long-chain fatty acids (VLCFA). Strongly affected cell types, such as oligodendrocytes, adrenocortical cells and macrophages, exhibit high cholesterol turnover. Here, we investigated how ABCD1 deficiency affects cholesterol metabolism in human X-ALD patient-derived fibroblasts and CNS tissues of Abcd1-deficient mice. Lipidome analyses revealed increased levels of cholesterol esters (CE), containing both saturated VLCFA and mono/polyunsaturated (V)LCFA. The elevated CE(26:0) and CE(26:1) levels remained unchanged in LXR agonist-treated Abcd1 KO mice despite reduced total C26:0. Under high-cholesterol loading, gene expression of SOAT1, converting cholesterol to CE and lipid droplet formation were increased in human X-ALD fibroblasts versus healthy control fibroblasts. However, the expression of NCEH1, catalysing CE hydrolysis and the cholesterol transporter ABCA1 and cholesterol efflux were also upregulated. Elevated Soat1 and Abca1 expression and lipid droplet content were confirmed in the spinal cord of X-ALD mice, where expression of the CNS cholesterol transporter Apoe was also elevated. The extent of peroxisome-lipid droplet co-localisation appeared low and was not impaired by ABCD1-deficiency in cholesterol-loaded primary fibroblasts. Finally, addressing steroidogenesis, progesterone-induced cortisol release was amplified in X-ALD fibroblasts. These results link VLCFA to cholesterol homeostasis and justify further consideration of therapeutic approaches towards reducing VLCFA and cholesterol levels in X-ALD.

Keywords:  ABCD1; Abcd1 KO mice; VLCFA; X-linked adrenoleukodystrophy; cholesterol esters; cortisol; lipid droplets; lipid metabolism; lipidomics

DOI:  https://doi.org/10.3390/biom13091333
J Neurochem. 2023 Sep 27.

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury.

Nathan R Strogulski, Luis V Portela, Brian M Polster, David J Loane.

  Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain-infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro- and anti-inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro-inflammatory activation is associated with decreased mitochondrial respiration, whereas anti-inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post-traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non-resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post-traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.

Keywords:  metabolism; microglia; mitochondria; neuroimmunology; traumatic brain injury

DOI:  https://doi.org/10.1111/jnc.15959
Neurotrauma Rep. 2023 ;4(1): 627-642

Characterizing Sex Differences in Mitochondrial Dysfunction After Severe Traumatic Brain Injury in Mice.

Olivia J Kalimon, Hemendra J Vekaria, Gopal V Velmurugan, W Brad Hubbard, Patrick G Sullivan.

  Traumatic brain injury (TBI) is caused by an impact or penetrating injury to the head resulting in abnormal brain function. Mitochondrial dysfunction is an important hallmark of TBI and has been thoroughly studied in male rodent models of brain injury, but relatively little is known about these outcomes in females. These studies were designed to examine sex as a biological variable for mitochondria-related outcomes after the severe controlled cortical impact (CCI) mouse model of TBI. Synaptic and non-synaptic mitochondria were isolated from the sham- or CCI-injured cortex as well as the hippocampus ipsilateral to the craniotomy 3, 12, 24, or 48 h post-surgery, and then bioenergetics were measured. Subtle variations were observed in the timeline of mitochondrial dysfunction between sexes. Non-synaptic cortical mitochondria from injured females showed early impairment at 12 h post-CCI compared to mitochondria from injured males at 24 h post-CCI. Contrastingly, in the synaptic fraction, mitochondria from injured males showed early impairment at 12 h post-CCI, whereas mitochondria from injured females showed impairment at 24 h post-CCI. Based on bioenergetic impairments at 24 h post-CCI, synaptic and non-synaptic mitochondrial calcium loading was also measured at this time point. Consistent with bioenergetic data at 24 h, non-synaptic mitochondria from injured males had increased calcium loading compared to uninjured control, but this effect was not observed in females. Finally, histological assessment of cortical tissue sparing in each sex was measured at 7 days post-injury. There was a lack of sex-based differences in cortical tissue sparing after severe CCI. Overall, there were some subtle sex differences in mitochondrial outcomes after CCI, but these findings were not statistically significant. This study highlights the importance of utilizing both sexes when measuring mitochondrial function after severe CCI.

Keywords:  CNS injury; calcium loading; mitochondrial bioenergetics; time course

DOI:  https://doi.org/10.1089/neur.2023.0046
Psychopharmacology (Berl). 2023 Sep 25.

Inhibition of fatty acid binding protein-5 in the basolateral amygdala induces anxiolytic effects and accelerates fear memory extinction.

Matthew J Jones, Taygun C Uzuneser, Timothy Clement, Hehe Wang, Iwao Ojima, Walter J Rushlow, Steven R Laviolette.

  RATIONALE: The endocannabinoid (eCB) system critically controls anxiety and fear-related behaviours. Anandamide (AEA), a prominent eCB ligand, is a hydrophobic lipid that requires chaperone proteins such as Fatty Acid Binding Proteins (FABPs) for intracellular transport. Intracellular AEA transport is necessary for degradation, so blocking FABP activity increases AEA neurotransmission.OBJECTIVE: To investigate the effects of a novel FABP5 inhibitor (SBFI-103) in the basolateral amygdala (BLA) on anxiety and fear memory.
METHODS: We infused SBFI-103 (0.5 μg-5 μg) to the BLA of adult male Sprague Dawley rats and ran various anxiety and fear memory behavioural assays, neurophysiological recordings, and localized molecular signaling analyses. We also co-infused SBFI-103 with the AEA inhibitor, LEI-401 (3 μg and 10 μg) to investigate the potential role of AEA in these phenomena.
RESULTS: Acute intra-BLA administration of SBFI-103 produced strong anxiolytic effects across multiple behavioural tests. Furthermore, animals exhibited acute and long-term accelerated associative fear memory extinction following intra-BLA FABP5 inhibition. In addition, BLA FABP5 inhibition induced strong modulatory effects on putative PFC pyramidal neurons along with significantly increased gamma oscillation power. Finally, we observed local BLA changes in the phosphorylation activity of various anxiety- and fear memory-related molecular biomarkers in the PI3K/Akt and MAPK/Erk signaling pathways. At all three levels of analyses, we found the functional effects of SBFI-103 depend on availability of the AEA ligand.
CONCLUSIONS: These findings demonstrate a novel intra-BLA FABP5 signaling mechanism regulating anxiety and fear memory behaviours, neuronal activity states, local anxiety-related molecular pathways, and functional AEA modulation.

Keywords:  Anandamide; Anxiety; Basolateral amygdala; Behavioural pharmacology; Endocannabinoid system; Fear memory; In vivo electrophysiology

DOI:  https://doi.org/10.1007/s00213-023-06468-7
Nutrients. 2023 Sep 17. pii: 4023. [Epub ahead of print]15(18):

Aspartic Acid in Health and Disease.

Milan Holeček.

  Aspartic acid exists in L- and D-isoforms (L-Asp and D-Asp). Most L-Asp is synthesized by mitochondrial aspartate aminotransferase from oxaloacetate and glutamate acquired by glutamine deamidation, particularly in the liver and tumor cells, and transamination of branched-chain amino acids (BCAAs), particularly in muscles. The main source of D-Asp is the racemization of L-Asp. L-Asp transported via aspartate-glutamate carrier to the cytosol is used in protein and nucleotide synthesis, gluconeogenesis, urea, and purine-nucleotide cycles, and neurotransmission and via the malate-aspartate shuttle maintains NADH delivery to mitochondria and redox balance. L-Asp released from neurons connects with the glutamate-glutamine cycle and ensures glycolysis and ammonia detoxification in astrocytes. D-Asp has a role in brain development and hypothalamus regulation. The hereditary disorders in L-Asp metabolism include citrullinemia, asparagine synthetase deficiency, Canavan disease, and dicarboxylic aminoaciduria. L-Asp plays a role in the pathogenesis of psychiatric and neurologic disorders and alterations in BCAA levels in diabetes and hyperammonemia. Further research is needed to examine the targeting of L-Asp metabolism as a strategy to fight cancer, the use of L-Asp as a dietary supplement, and the risks of increased L-Asp consumption. The role of D-Asp in the brain warrants studies on its therapeutic potential in psychiatric and neurologic disorders.

Keywords:  aspartame; aspartate and cell-to-cell interactions; branched-chain amino acids; gluconeogenesis; glutamate–glutamine cycle; malate–aspartate shuttle; neurotransmission; oxaloacetate; purine-nucleotide cycle; urea cycle

DOI:  https://doi.org/10.3390/nu15184023
Autophagy. 2023 Sep 28. 1-20

The lipid basis of cell death and autophagy.

Zhi Lin, Fei Long, Rui Kang, Daniel J Klionsky, Minghua Yang, Daolin Tang.

  ABBREVIATIONS: ACSL: acyl-CoA synthetase long chain family; DISC: death-inducing signaling complex; DAMPs: danger/damage-associated molecular patterns; Dtgn: dispersed trans-Golgi network; FAR1: fatty acyl-CoA reductase 1; GPX4: glutathione peroxidase 4; LPCAT3: lysophosphatidylcholine acyltransferase 3; LPS: lipopolysaccharide; MUFAs: monounsaturated fatty acids; MOMP: mitochondrial outer membrane permeabilization; MLKL, mixed lineage kinase domain like pseudokinase; oxPAPC: oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine; OxPCs: oxidized phosphatidylcholines; PUFAs: polyunsaturated fatty acids; POR: cytochrome p450 oxidoreductase; PUFAs: polyunsaturated fatty acids; RCD: regulated cell death; RIPK1: receptor interacting serine/threonine kinase 1; SPHK1: sphingosine kinase 1; SOAT1: sterol O-acyltransferase 1; SCP2: sterol carrier protein 2; SFAs: saturated fatty acids; SLC47A1: solute carrier family 47 member 1; SCD: stearoyl-CoA desaturase; VLCFA: very long chain fatty acids.

Keywords:  Apoptosis; autophagy; cell death; lipid metabolism; pathway

DOI:  https://doi.org/10.1080/15548627.2023.2259732
Front Aging Neurosci. 2023 ;15 1194203

BACE1 and SCD1 are associated with neurodegeneration.

Ferley A Bedoya-Guzmán, Mar Pacheco-Herrero, Ivan Daniel Salomon-Cruz, Angela Maria Barrera-Sandoval, Johanna Andrea Gutierrez Vargas, Javier Gustavo Villamil-Ortiz, Carlos Andres Villegas Lanau, Julián David Arias-Londoño, Estela Area-Gomez, Gloria Patricia Cardona Gomez.

  Introduction: Proteolytic processing of amyloid protein precursor by β-site secretase enzyme (BACE1) is dependent on the cellular lipid composition and is affected by endomembrane trafficking in dementia and Alzheimer's disease (AD). Stearoyl-CoA desaturase 1 (SCD1) is responsible for the synthesis of fatty acid monounsaturation (MUFAs), whose accumulation is strongly associated with cognitive dysfunction.Methods: In this study, we analyzed the relationship between BACE1 and SCD1 in vivo and in vitro neurodegenerative models and their association in familial AD (FAD), sporadic AD (SAD), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) using microscopy, biochemical, and mass SPECT approach.
Results: Our findings showed that BACE1 and SCD1 immunoreactivities were increased and colocalized in astrocytes of the hippocampus in a rat model of global cerebral ischemia (2-VO). A synergistic effect of double BACE1/SCD1 silencing on the recovery of motor and cognitive functions was obtained. This neuroprotective regulation involved the segregation of phospholipids (PLs) associated with polyunsaturated fatty acids in the hippocampus, cerebrospinal fluid, and serum. The double silencing in the sham and ischemic groups was stronger in the serum, inducing an inverse ratio between total phosphatydilcholine (PC) and lysophosphatidylcholine (LPC), represented mainly by the reduction of PC 38:4 and PC 36:4 and an increase in LPC 16:0 and LPC 18:0. Furthermore, PC 38:4 and PC:36:4 levels augmented in pathological conditions in in vitro AD models. BACE1 and SCD1 increases were confirmed in the hippocampus of FAD, SAD, and CADASIL.
Conclusion: Therefore, the findings suggest a novel convergence of BACE-1 and SCD1 in neurodegeneration, related to pro-inflammatory phospholipids.

Keywords:  BACE1; PUFAs; SCD1; neurodegeneration; phospholipids; pro-inflammation

DOI:  https://doi.org/10.3389/fnagi.2023.1194203
Front Neurosci. 2023 ;17 1231584

Pharmacological rescue of mitochondrial and neuronal defects in SPG7 hereditary spastic paraplegia patient neurons using high throughput assays.

Gautam Wali, Yan Li, Erandhi Liyanage, Kishore R Kumar, Margot L Day, Carolyn M Sue.

  SPG7 is the most common form of autosomal recessive hereditary spastic paraplegia (HSP). There is a lack of HSP-SPG7 human neuronal models to understand the disease mechanism and identify new drug treatments. We generated a human neuronal model of HSP-SPG7 using induced pluripotent stem (iPS) cell technology. We first generated iPS cells from three HSP-SPG7 patients carrying different disease-causing variants and three healthy controls. The iPS cells were differentiated to form neural progenitor cells (NPCs) and then from NPCs to mature cortical neurons. Mitochondrial and neuronal defects were measured using a high throughout imaging and analysis-based assay in live cells. Our results show that compared to control NPCs, patient NPCs had aberrant mitochondrial morphology with increased mitochondrial size and reduced membrane potential. Patient NPCs develop to form mature cortical neurons with amplified mitochondrial morphology and functional defects along with defects in neuron morphology - reduced neurite complexity and length, reduced synaptic gene, protein expression and activity, reduced viability and increased axonal degeneration. Treatment of patient neurons with Bz-423, a mitochondria permeability pore regulator, restored the mitochondrial and neurite morphological defects and mitochondrial membrane potential back to control neuron levels and rescued the low viability and increased degeneration in patient neurons. This study establishes a direct link between mitochondrial and neuronal defects in HSP-SPG7 patient neurons. We present a strategy for testing mitochondrial targeting drugs to rescue neuronal defects in HSP-SPG7 patient neurons.

Keywords:  cortical neurons; hereditary spastic paraplegia (HSP); high throughput imaging (HTI); induced pluripotent stem (iPS) cell; mitochondria

DOI:  https://doi.org/10.3389/fnins.2023.1231584
Trends Mol Med. 2023 Sep 26. pii: S1471-4914(23)00216-2. [Epub ahead of print]

d-Amino acids: new clinical pathways for brain diseases.

Isis Nem de Oliveira Souza, Robin Roychaudhuri, Jacqueline de Belleroche, Jean-Pierre Mothet.

  Free d-amino acids (d-AAs) are emerging as a novel and important class of signaling molecules in many organs, including the brain and endocrine systems. There has been considerable progress in our understanding of the fundamental roles of these atypical messengers, with increasingly recognized implications in a wide range of neuropathologies, including schizophrenia (SCZ), epilepsy, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), substance abuse, and chronic pain, among others. Research has enabled the discovery that d-serine, d-aspartate and more recently d-cysteine are essential for the healthy development and function of the central nervous system (CNS). We discuss recent progress that has profoundly transformed our vision of numerous physiological processes but has also shown how d-AAs are now offering therapeutic promise in clinical settings for several human diseases.

Keywords:  SNPs; drug discovery; metabolism; neurodegenerative diseases; neurological disorders; synapse

DOI:  https://doi.org/10.1016/j.molmed.2023.09.001
Cell Mol Life Sci. 2023 Sep 25. 80(10): 302

Metabolic and cell cycle shift induced by the deletion of Dnm1l attenuates the dissolution of pluripotency in mouse embryonic stem cells.

Bong Jong Seo, Seung Bin Na, Joonhyuk Choi, Byeongyong Ahn, Omer Habib, Chankyu Park, Kwonho Hong, Jeong Tae Do.

  Mitochondria are versatile organelles that continuously change their morphology via fission and fusion. However, the detailed functions of mitochondrial dynamics-related genes in pluripotent stem cells remain largely unclear. Here, we aimed to determine the effects on energy metabolism and differentiation ability of mouse embryonic stem cells (ESCs) following deletion of the mitochondrial fission-related gene Dnml1. Resultant Dnm1l-/- ESCs maintained major pluripotency characteristics. However, Dnm1l-/- ESCs showed several phenotypic changes, including the inhibition of differentiation ability (dissolution of pluripotency). Notably, Dnm1l-/- ESCs maintained the expression of the pluripotency marker Oct4 and undifferentiated colony types upon differentiation induction. RNA sequencing analysis revealed that the most frequently differentially expressed genes were enriched in the glutathione metabolic pathway. Our data suggested that differentiation inhibition of Dnm1l-/- ESCs was primarily due to metabolic shift from glycolysis to OXPHOS, G2/M phase retardation, and high level of Nanog and 2-cell-specific gene expression.

Keywords:  Cellular metabolism; Dynamin 1 like (Dnm1l); Embryonic stem cells (ESCs); Mitochondrial fission; Pluripotency

DOI:  https://doi.org/10.1007/s00018-023-04962-x
Biochem Soc Trans. 2023 Sep 28. pii: BST20221455. [Epub ahead of print]

The role of lipid scramblases in regulating lipid distributions at cellular membranes.

Yicheng Wang, Taroh Kinoshita.

  Glycerophospholipids, sphingolipids and cholesterol assemble into lipid bilayers that form the scaffold of cellular membranes, in which proteins are embedded. Membrane composition and membrane protein profiles differ between plasma and intracellular membranes and between the two leaflets of a membrane. Lipid distributions between two leaflets are mediated by lipid translocases, including flippases and scramblases. Flippases use ATP to catalyze the inward movement of specific lipids between leaflets. In contrast, bidirectional flip-flop movements of lipids across the membrane are mediated by scramblases in an ATP-independent manner. Scramblases have been implicated in disrupting the lipid asymmetry of the plasma membrane, protein glycosylation, autophagosome biogenesis, lipoprotein secretion, lipid droplet formation and communications between organelles. Although scramblases in plasma membranes were identified over 10 years ago, most progress about scramblases localized in intracellular membranes has been made in the last few years. Herein, we review the role of scramblases in regulating lipid distributions in cellular membranes, focusing primarily on intracellular membrane-localized scramblases.

Keywords:  flippase; glycolipids; lipid transfer; phospholipids; post translational modification; scramblase

DOI:  https://doi.org/10.1042/BST20221455
Cells. 2023 Sep 19. pii: 2314. [Epub ahead of print]12(18):

Inborn Errors of Metabolism with Ataxia: Current and Future Treatment Options.

Tatiana Bremova-Ertl, Jan Hofmann, Janine Stucki, Anja Vossenkaul, Matthias Gautschi.

  A number of hereditary ataxias are caused by inborn errors of metabolism (IEM), most of which are highly heterogeneous in their clinical presentation. Prompt diagnosis is important because disease-specific therapies may be available. In this review, we offer a comprehensive overview of metabolic ataxias summarized by disease, highlighting novel clinical trials and emerging therapies with a particular emphasis on first-in-human gene therapies. We present disease-specific treatments if they exist and review the current evidence for symptomatic treatments of these highly heterogeneous diseases (where cerebellar ataxia is part of their phenotype) that aim to improve the disease burden and enhance quality of life. In general, a multimodal and holistic approach to the treatment of cerebellar ataxia, irrespective of etiology, is necessary to offer the best medical care. Physical therapy and speech and occupational therapy are obligatory. Genetic counseling is essential for making informed decisions about family planning.

Keywords:  GM2-gangliosidosis; Niemann-Pick type C; abetalipoproteinemia; acetyl-DL-leucine; acetyl-L-leucine; biomarkers; cerebellar ataxia; cerebrotendinous xanthomatosis; disease-modifying treatment; disorders of carbohydrate metabolism; hereditary metabolic ataxia; inborn error of metabolism; lysosomal storage disorders; metabolic diseases; neurodegeneration; neuroprotection; ocular motor; symptomatic treatment

DOI:  https://doi.org/10.3390/cells12182314
Biomedicines. 2023 Aug 26. pii: 2388. [Epub ahead of print]11(9):

Porcine Astrocytes and Their Relevance for Translational Neurotrauma Research.

Erin M Purvis, Natalia Fedorczak, Annette Prah, Daniel Han, John C O'Donnell.

  Astrocytes are essential to virtually all brain processes, from ion homeostasis to neurovascular coupling to metabolism, and even play an active role in signaling and plasticity. Astrocytic dysfunction can be devastating to neighboring neurons made inherently vulnerable by their polarized, excitable membranes. Therefore, correcting astrocyte dysfunction is an attractive therapeutic target to enhance neuroprotection and recovery following acquired brain injury. However, the translation of such therapeutic strategies is hindered by a knowledge base dependent almost entirely on rodent data. To facilitate additional astrocytic research in the translatable pig model, we present a review of astrocyte findings from pig studies of health and disease. We hope that this review can serve as a road map for intrepid pig researchers interested in studying astrocyte biology.

Keywords:  astrocytes; glia; pig; porcine; swine; translational neurotrauma

DOI:  https://doi.org/10.3390/biomedicines11092388