bims-medebr 2022-12-25 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–12–25
29 papers selected by
Regina F. Fernández, Johns Hopkins University

Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte-derived lipid transport.
The Impact of Nicotine along with Oral Contraceptive Exposure on Brain Fatty Acid Metabolism in Female Rats.
Mitochondrial sodium/calcium exchanger NCLX regulates glycolysis in astrocytes, impacting on cognitive performance.
Overexpression of UCP4 in astrocytic mitochondria prevents multilevel dysfunctions in a mouse model of Alzheimer's disease.
Ketogenic Diet for Neonatal Hypoxic-Ischemic Encephalopathy.
Magnetic resonance spectroscopy studies in migraine.
Microglia and Cholesterol Handling: Implications for Alzheimer's Disease.
The Polyunsaturated Fatty Acid EPA, but Not DHA, Enhances Neurotrophic Factor Expression through Epigenetic Mechanisms and Protects against Parkinsonian Neuronal Cell Death.
Mechanistic model for human brain metabolism and its connection to the neurovascular coupling.
The multiple facets of acetyl-CoA metabolism: Energetics, biosynthesis, regulation, acylation and inborn errors.
Intracerebroventricular high doses of TRIAC at juvenile stages improve peripheral hyperthyroidism and mediate thyromimetic effects in limited brain regions in a mouse model of MCT8 deficiency.
Imaging of lactate metabolism in retinal Müller cells with a FRET nanosensor.
Lipid Alterations in Glioma: A Systematic Review.
Pathogenic variants of the coenzyme A biosynthesis-associated enzyme phosphopantothenoylcysteine decarboxylase (PPCDC) cause autosomal-recessive dilated cardiomyopathy.
Effects of aging and long-term physical activity on mitochondrial physiology and redox state of the cortex and cerebellum of female rats.
Role for Astrocytes in mGluR-Dependent LTD in the Neocortex and Hippocampus.
A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy.
Effect of β-hydroxybutyrate on behavioral alterations, molecular and morphological changes in CNS of multiple sclerosis mouse model.
Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation.
Endogenous d-serine exists in the mammalian brain independent of synthesis by serine racemase.
Reduced D2 /D3 Receptor Binding and Glucose Metabolism in a Macaque Model of Huntington's Disease.
N-Acetylcysteine Administration Attenuates Sensorimotor Impairments Following Neonatal Hypoxic-Ischemic Brain Injury in Rats.
APOE2 Exacerbates TDP-43 Related Toxicity in the Absence of Alzheimer Pathology.
Amelioration of central neurodegeneration by docosahexaenoic acid in trigeminal neuralgia rats through the regulation of central neuroinflammation.
Mitochondrial signaling on innate immunity activation in Parkinson disease.
Do renal and cardiac malformations in the fetus signal carnitine palmitoyltransferase II deficiency? A rare lethal fatty acid oxidation defect.
A method to estimate the cellular composition of the mouse brain from heterogeneous datasets.
Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases.
Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity.

J Neurochem. 2022 Dec 22.

Apolipoprotein E ε4 disrupts oligodendrocyte differentiation by interfering with astrocyte-derived lipid transport.

Kingston King-Shi Mok, Sunny Hoi-Sang Yeung, Gerald Wai-Yeung Cheng, Iris Wai-Ting Ma, Ralph Hon-Sun Lee, Karl Herrup, Kai-Hei Tse.

  Carriers of the APOE4 (Apolipoprotein E ε4) variant of the APOE gene are subject to several age-related health risks, including Alzheimer's disease (AD). The deficient lipid and cholesterol transport capabilities of the APOE4 protein are one reason for the altered risk profile. In particular, APOE4 carriers are at elevated risk for sporadic Alzheimer's disease (AD). While deposits o misfolded proteins are present in the AD brain, white matter (WM) myelin is also disturbed. As myelin is a lipid- and cholesterol-rich structure, the connection to APOE makes considerable biological sense. To explore the APOE-WM connection, we have analyzed the impact of human APOE4 on oligodendrocytes (OLs) of the mouse both in vivo and in vitro. We find that APOE proteins is enriched in astrocytes but sparse in OL. In human APOE4 (hAPOE4) knockin mice, myelin lipid content is increased but the density of major myelin proteins (MBP, MAG and PLP) is largely unchanged. We also find an unexpected but significant reduction of cell density of the OL lineage (Olig2+ ) and an abnormal accumulation of OL precursors (Nkx 2.2+ ), suggesting a disruption of OL differentiation. Gene ontology analysis of an existing RNA-seq dataset confirms a robust transcriptional response to the altered chemistry of the hAPOE4 mouse brain. In culture, the uptake of astrocyte-derived APOE during Lovastatin-mediated depletion of cholesterol synthesis is sufficient to sustain OL differentiation. While endogenous hAPOE protein isoforms have no effects on OL development, exogenous hAPOE4 abolishes the ability of very low-density lipoprotein to restore myelination in Apoe-deficient, cholesterol-depleted OL. Our data suggest that APOE4 impairs myelination in the aging brain by interrupting the delivery of astrocyte-derived lipids to the oligodendrocytes. We propose that high myelin turnover and OL exhaustion found in APOE4 carriers is a likely explanation for the APOE-dependent myelin phenotypes of the AD brain.

Keywords:  APOE4; Alzheimer's disease; Astrocyte; Lipid transport; Myelin; Oligodendrocyte

DOI:  https://doi.org/10.1111/jnc.15748
Int J Mol Sci. 2022 Dec 16. pii: 16075. [Epub ahead of print]23(24):

The Impact of Nicotine along with Oral Contraceptive Exposure on Brain Fatty Acid Metabolism in Female Rats.

Shahil H Patel, Alba Timón-Gómez, Hari Pradhyumnan, Berk Mankaliye, Kunjan R Dave, Miguel A Perez-Pinzon, Ami P Raval.

  Smoking-derived nicotine (N) and oral contraceptive (OC) synergistically exacerbate ischemic brain damage in females, and the underlying mechanisms remain elusive. In a previous study, we showed that N + OC exposure altered brain glucose metabolism in females. Since lipid metabolism complements glycolysis, the current study aims to examine the metabolic fingerprint of fatty acids in the brain of female rats exposed to N+/-OC. Adolescent and adult Sprague-Dawley female rats were randomly (n = 8 per group) exposed to either saline or N (4.5 mg/kg) +/-OC (combined OC or placebo delivered via oral gavage) for 16-21 days. Following exposure, brain tissue was harvested for unbiased metabolomic analysis (performed by Metabolon Inc., Morrisville, NC, USA) and the metabolomic profile changes were complemented with Western blot analysis of key enzymes in the lipid pathway. Metabolomic data showed significant accumulation of fatty acids and phosphatidylcholine (PC) metabolites in the brain. Adolescent, more so than adult females, exposed to N + OC showed significant increases in carnitine-conjugated fatty acid metabolites compared to saline control animals. These changes in fatty acyl carnitines were accompanied by an increase in a subset of free fatty acids, suggesting elevated fatty acid β-oxidation in the mitochondria to meet energy demand. In support, β-hydroxybutyrate was significantly lower in N + OC exposure groups in adolescent animals, implying a complete shunting of acetyl CoA for energy production via the TCA cycle. The reported changes in fatty acids and PC metabolism due to N + OC could inhibit post-translational palmitoylation of membrane proteins and synaptic vesicle formation, respectively, thus exacerbating ischemic brain damage in female rats.

Keywords:  carnitine palmitoyltransferase enzymes 1 and 2; metabolomics; nicotine; oral contraceptive; palmitoylation; phosphatidylcholine; phospholipids; stroke; β-oxidation

DOI:  https://doi.org/10.3390/ijms232416075
J Neurochem. 2022 Dec 23.

Mitochondrial sodium/calcium exchanger NCLX regulates glycolysis in astrocytes, impacting on cognitive performance.

João Victor Cabral-Costa, Carlos Vicente-Gutiérrez, Jesús Agulla, Rebeca Lapresa, John W Elrod, Ángeles Almeida, Juan P Bolaños, Alicia J Kowaltowski.

  Intracellular Ca2+ concentrations are strictly controlled by plasma membrane transporters, the endoplasmic reticulum, and mitochondria, in which Ca2+ uptake is mediated by the mitochondrial calcium uniporter complex (MCUc), while efflux occurs mainly through the mitochondrial Na+ /Ca2+ exchanger (NCLX). RNAseq database repository searches led us to identify the Nclx transcript as highly enriched in astrocytes when compared to neurons. To assess the role of NCLX in mouse primary culture astrocytes, we inhibited its function both pharmacologically or genetically. This resulted in re-shaping of cytosolic Ca2+ signaling and a metabolic shift that increased glycolytic flux and lactate secretion in a Ca2+ -dependent manner. Interestingly, in vivo genetic deletion of NCLX in hippocampal astrocytes improved cognitive performance in behavioral tasks, whereas hippocampal neuron-specific deletion of NCLX impaired cognitive performance. These results unveil a role for NCLX as a novel modulator of astrocytic glucose metabolism, impacting on cognition.

Keywords:  NCLX; astrocyte; brain metabolism; calcium transport; energy metabolism; glycolysis; lactate; metabolic regulation; mitochondrial metabolism; sodium transport; sodium-calcium exchange

DOI:  https://doi.org/10.1111/jnc.15745
Glia. 2022 Dec 20.

Overexpression of UCP4 in astrocytic mitochondria prevents multilevel dysfunctions in a mouse model of Alzheimer's disease.

Nadia Rosenberg, Maria Reva, Francesca Binda, Leonardo Restivo, Pauline Depierre, Julien Puyal, Marc Briquet, Yann Bernardinelli, Anne-Bérengère Rocher, Henry Markram, Jean-Yves Chatton.

  Alzheimer's disease (AD) is becoming increasingly prevalent worldwide. It represents one of the greatest medical challenges as no pharmacologic treatments are available to prevent disease progression. Astrocytes play crucial functions within neuronal circuits by providing metabolic and functional support, regulating interstitial solute composition, and modulating synaptic transmission. In addition to these physiological functions, growing evidence points to an essential role of astrocytes in neurodegenerative diseases like AD. Early-stage AD is associated with hypometabolism and oxidative stress. Contrary to neurons that are vulnerable to oxidative stress, astrocytes are particularly resistant to mitochondrial dysfunction and are therefore more resilient cells. In our study, we leveraged astrocytic mitochondrial uncoupling and examined neuronal function in the 3xTg AD mouse model. We overexpressed the mitochondrial uncoupling protein 4 (UCP4), which has been shown to improve neuronal survival in vitro. We found that this treatment efficiently prevented alterations of hippocampal metabolite levels observed in AD mice, along with hippocampal atrophy and reduction of basal dendrite arborization of subicular neurons. This approach also averted aberrant neuronal excitability observed in AD subicular neurons and preserved episodic-like memory in AD mice assessed in a spatial recognition task. These findings show that targeting astrocytes and their mitochondria is an effective strategy to prevent the decline of neurons facing AD-related stress at the early stages of the disease.

Keywords:  astrocytes; mitochondrial uncoupling proteins; neurodegenerative diseases; neuronal excitability; spatial memory

DOI:  https://doi.org/10.1002/glia.24317
ACS Chem Neurosci. 2022 Dec 21.

Ketogenic Diet for Neonatal Hypoxic-Ischemic Encephalopathy.

Yue Zhou, Luqiang Sun, Haichuan Wang.

  The prevalence of neonatal hypoxic-ischemic encephalopathy (HIE), a devastating neurological injury, is increasing; thus, effective treatments and preventions are urgently needed. The underlying pathology of HIE remains unclear; recent research has focused on elucidating key features of the disease. A variety of diseases can be alleviated by consuming a ketogenic diet (KD) despite differences in pathogenesis and features, given the common mechanisms of KD-induced effects. Dietary modification is the most translatable, cost-efficient, and safest approach to treat acute or chronic neurological disorders and reduces reliance on pharmaceutical treatments. Evidence suggests that the KD can exert beneficial effects in animal models and in humans with brain injuries. The efficacy of the KD in preventing neuronal damage, motor alterations, and cognitive decline varies. Moreover, the KD may provide an alternative source of energy, enhance mitochondrial function, and reduce the expression of inflammatory and apoptotic mediators. Thus, this diet has attracted interest as a potential therapy for HIE. This review examined the role of the KD in HIE treatment and described the mechanisms by which ketone bodies (KBs) exert effects under pathological conditions and protect against brain damage; the evidence supports the implementation of dietary interventions as a therapeutic strategy for HIE. Future research should aim to elucidate the underlying mechanisms of the KD in patients with HIE and determine whether the effect of the KD on clinical outcomes can be reproduced in humans.

Keywords:  Hypoxic−ischemic; cerebral metabolism; encephalopathy; ketogenic diet; neuroprotective strategy

DOI:  https://doi.org/10.1021/acschemneuro.2c00609
Neurobiol Pain. 2022 Aug-Dec;12:12 100102

Magnetic resonance spectroscopy studies in migraine.

Simona Nikolova, Todd J Schwedt.

  This review summarizes major findings and recent advances in magnetic resonance spectroscopy (MRS) of migraine. A multi database search of PubMed, EMBASE, and Web of Science was performed with variations of magnetic resonance spectroscopy and headache until 20th September 2021. The search generated 2897 studies, 676 which were duplicates and 1836 were not related to headache. Of the remaining 385 studies examined, further exclusions for not migraine (n = 114), and not MRS of human brain (n = 128), and non-original contributions (n = 51) or conferences (n = 24) or case studies (n = 11) or non-English (n = 3), were applied. The manuscripts of all resulting reports were reviewed for their possible inclusion in this manuscript (n = 54). The reference lists of all included reports were carefully reviewed and articles relevant to this review were added (n = 2).Included are 56 studies of migraine with and without aura that involve magnetic resonance spectroscopy of the human brain. The topics are presented in the form of a narrative review. This review aims to provide a summary of the metabolic changes measured by MRS in patients with migraine. Despite the variability reported between studies, common findings focused on regions functionally relevant to migraine such as occipital cortices, thalamic nuclei, cerebellum and cingulate. The most reproducible results were decreased N-acetyl-aspartate (NAA) in cerebellum in patients with hemiplegic migraine and in the thalamus of chronic migraine patients. Increased lactate (Lac) in the occipital cortex was found for migraine with aura but not in subjects without aura. MRS studies support the hypothesis of impaired energetics and mitochondrial dysfunction in migraine. Although results regarding GABA and Glu were less consistent, studies suggest there might be an imbalance of these important inhibitory and excitatory neurotransmitters in the migraine brain. Multinuclear imaging studies in migraine with and without aura, predominantly investigating phosphorous, report alterations of PCr in occipital, parietal, and posterior brain regions. There have been too few studies to assess the diagnostic relevance of sodium imaging in migraine.

Keywords:  1H-MRS; 31P-MRS; Headache; MRS; Metabolic; Migraine

DOI:  https://doi.org/10.1016/j.ynpai.2022.100102
Biomedicines. 2022 Dec 01. pii: 3105. [Epub ahead of print]10(12):

Microglia and Cholesterol Handling: Implications for Alzheimer's Disease.

Oscar M Muñoz Herrera, Angela M Zivkovic.

  Cholesterol is essential for brain function and structure, however altered cholesterol metabolism and transport are hallmarks of multiple neurodegenerative conditions, including Alzheimer's disease (AD). The well-established link between apolipoprotein E (APOE) genotype and increased AD risk highlights the importance of cholesterol and lipid transport in AD etiology. Whereas more is known about the regulation and dysregulation of cholesterol metabolism and transport in neurons and astrocytes, less is known about how microglia, the immune cells of the brain, handle cholesterol, and the subsequent implications for the ability of microglia to perform their essential functions. Evidence is emerging that a high-cholesterol environment, particularly in the context of defects in the ability to transport cholesterol (e.g., expression of the high-risk APOE4 isoform), can lead to chronic activation, increased inflammatory signaling, and reduced phagocytic capacity, which have been associated with AD pathology. In this narrative review we describe how cholesterol regulates microglia phenotype and function, and discuss what is known about the effects of statins on microglia, as well as highlighting areas of future research to advance knowledge that can lead to the development of novel therapies for the prevention and treatment of AD.

Keywords:  Alzheimer’s disease; cholesterol; microglia

DOI:  https://doi.org/10.3390/biomedicines10123105
Int J Mol Sci. 2022 Dec 19. pii: 16176. [Epub ahead of print]23(24):

The Polyunsaturated Fatty Acid EPA, but Not DHA, Enhances Neurotrophic Factor Expression through Epigenetic Mechanisms and Protects against Parkinsonian Neuronal Cell Death.

Maria Rachele Ceccarini, Veronica Ceccarelli, Michela Codini, Katia Fettucciari, Mario Calvitti, Samuela Cataldi, Elisabetta Albi, Alba Vecchini, Tommaso Beccari.

  ω-3 Polyunsaturated fatty acids (PUFAs) have been found to exert many actions, including neuroprotective effects. In this regard, the exact molecular mechanisms are not well understood. Parkinson's disease (PD) is the second most common age-related neurodegenerative disease. Emerging evidence supports the hypothesis that PD is the result of complex interactions between genetic abnormalities, environmental toxins, mitochondrial dysfunction, and other cellular processes, such as DNA methylation. In this context, BDNF (brain-derived neurotrophic factor) and GDNF (glial cell line-derived neurotrophic factor) have a pivotal role because they are both involved in neuron differentiation, survival, and synaptogenesis. In this study, we aimed to elucidate the potential role of two PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and their effects on BDNF and GDNF expression in the SH-SY5Y cell line. Cell viability was determined using the MTT assay, and flow cytometry analysis was used to verify the level of apoptosis. Transmission electron microscopy was performed to observe the cell ultrastructure and mitochondria morphology. BDNF and GDNF protein levels and mRNA were assayed by Western blotting and RT-PCR, respectively. Finally, methylated and hydroxymethylated DNA immunoprecipitation were performed in the BDNF and GDNF promoter regions. EPA, but not DHA, is able (i) to reduce the neurotoxic effect of neurotoxin 6-hydroxydopamine (6-OHDA) in vitro, (ii) to re-establish mitochondrial function, and (iii) to increase BNDF and GDNF expression via epigenetic mechanisms.

Keywords:  BDNF; DHA; DNA methylation; EPA; GDNF; PUFAs; Parkinson’s disease; apoptosis; mitochondrial damage; neurodegeneration

DOI:  https://doi.org/10.3390/ijms232416176
PLoS Comput Biol. 2022 Dec 22. 18(12): e1010798

Mechanistic model for human brain metabolism and its connection to the neurovascular coupling.

Nicolas Sundqvist, Sebastian Sten, Peter Thompson, Benjamin Jan Andersson, Maria Engström, Gunnar Cedersund.

The neurovascular and neurometabolic couplings (NVC and NMC) connect cerebral activity, blood flow, and metabolism. This interconnection is used in for instance functional imaging, which analyses the blood-oxygen-dependent (BOLD) signal. The mechanisms underlying the NVC are complex, which warrants a model-based analysis of data. We have previously developed a mechanistically detailed model for the NVC, and others have proposed detailed models for cerebral metabolism. However, existing metabolic models are still not fully utilizing available magnetic resonance spectroscopy (MRS) data and are not connected to detailed models for NVC. Therefore, we herein present a new model that integrates mechanistic modelling of both MRS and BOLD data. The metabolic model covers central metabolism, using a minimal set of interactions, and can describe time-series data for glucose, lactate, aspartate, and glutamate, measured after visual stimuli. Statistical tests confirm that the model can describe both estimation data and predict independent validation data, not used for model training. The interconnected NVC model can simultaneously describe BOLD data and can be used to predict expected metabolic responses in experiments where metabolism has not been measured. This model is a step towards a useful and mechanistically detailed model for cerebral blood flow and metabolism, with potential applications in both basic research and clinical applications.

DOI: https://doi.org/10.1371/journal.pcbi.1010798
Mol Genet Metab. 2022 Nov 30. pii: S1096-7192(22)00442-5. [Epub ahead of print]138(1): 106966

The multiple facets of acetyl-CoA metabolism: Energetics, biosynthesis, regulation, acylation and inborn errors.

Youlin Wang, Hao Yang, Chloé Geerts, Alexandra Furtos, Paula Waters, Denis Cyr, Shupei Wang, Grant A Mitchell.

  Acetyl-coenzyme A (Ac-CoA) is a core metabolite with essential roles throughout cell physiology. These functions can be classified into energetics, biosynthesis, regulation and acetylation of large and small molecules. Ac-CoA is essential for oxidative metabolism of glucose, fatty acids, most amino acids, ethanol, and of free acetate generated by endogenous metabolism or by gut bacteria. Ac-CoA cannot cross lipid bilayers, but acetyl groups from Ac-CoA can shuttle across membranes as part of carrier molecules like citrate or acetylcarnitine, or as free acetate or ketone bodies. Ac-CoA is the basic unit of lipid biosynthesis, providing essentially all of the carbon for the synthesis of fatty acids and of isoprenoid-derived compounds including cholesterol, coenzyme Q and dolichols. High levels of Ac-CoA in hepatocytes stimulate lipid biosynthesis, ketone body production and the diversion of pyruvate metabolism towards gluconeogenesis and away from oxidation; low levels exert opposite effects. Acetylation changes the properties of molecules. Acetylation is necessary for the synthesis of acetylcholine, acetylglutamate, acetylaspartate and N-acetyl amino sugars, and to metabolize/eliminate some xenobiotics. Acetylation is a major post-translational modification of proteins. Different types of protein acetylation occur. The most-studied form occurs at the epsilon nitrogen of lysine residues. In histones, lysine acetylation can alter gene transcription. Acetylation of other proteins has diverse, often incompletely-documented effects. Inborn errors related to Ac-CoA feature a broad spectrum of metabolic, neurological and other features. To date, a small number of studies of animals with inborn errors of CoA thioesters has included direct measurement of acyl-CoAs. These studies have shown that low levels of tissue Ac-CoA correlate with the development of clinical signs, hinting that shortage of Ac-CoA may be a recurrent theme in these conditions. Low levels of Ac-CoA could potentially disrupt any of its roles.

Keywords:  Acetyl-CoA; Acetylation; Acylation; Energy metabolism; Inborn errors

DOI:  https://doi.org/10.1016/j.ymgme.2022.106966
Thyroid. 2022 Dec 23.

Intracerebroventricular high doses of TRIAC at juvenile stages improve peripheral hyperthyroidism and mediate thyromimetic effects in limited brain regions in a mouse model of MCT8 deficiency.

Carmen Grijota-Martínez, Ana Montero-Pedrazuela, Jorge Hidalgo-Álvarez, Soledad Bárez-López, Ana Guadaño-Ferraz.

INTRODUCTION: Patients lacking functional Monocarboxylate transporter 8 (MCT8), a highly specific thyroid hormone (TH) transporter, present severe psychomotor disabilities. MCT8 deficiency leads to peripheral hyperthyroidism and brain hypothyroidism, the latter due to impaired transport of TH across brain barriers. Available treatments for patients are limited and aim to overcome the limited TH transport across brain barriers. The use of TH analogues such as 3,3',5-triiodothyroacetic acid (TRIAC) that do not require MCT8 to cross the cellular membranes is considered a potential therapy for MCT8 deficiency. Previous studies have shown that systemic administration of TRIAC at therapeutic doses does not increase TRIAC content in the brain, while intracerebroventricular (ICV) administration of therapeutic doses of TRIAC increases TRIAC content in the brain but does not mediate thyromimetic effects. In view of this, we hypothesise that ICV administration of high doses of TRIAC can mediate thyromimetic effects in the brain without worsening the brain hypothyroidism or peripheral hyperthyroidism of patients.
METHODS: 400 ng/g of body weight per day of TRIAC were administered ICV to a mouse model of MCT8 deficiency: Mct8-/y and deiodinase 2 (Dio2)-/ - double knockout mice. The effects of this treatment on TH and TRIAC levels/content in blood and tissues were determined by radioimmunoassay and effects on TH-regulated genes were assessed by RT-qPCR in peripheral and central tissues.
RESULTS: ICV administration of high doses of TRIAC ameliorated the peripheral hyperthyroidism. In the brain, this treatment did not further aggravate brain hypothyroidism and increased TRIAC content in several brain regions; however, only moderate thyromimetic activity was observed in restricted brain areas.
CONCLUSION: Administration of high doses of TRIAC by ICV delivery at juvenile stages in a mouse model of MCT8 deficiency, is effective in normalising peripheral hyperthyroidism, but exerts minimal thyromimetic activity in the brain.

DOI: https://doi.org/10.1089/thy.2022.0562
Exp Eye Res. 2022 Dec 14. pii: S0014-4835(22)00433-X. [Epub ahead of print]226 109352

Imaging of lactate metabolism in retinal Müller cells with a FRET nanosensor.

Víctor Calbiague García, Yiyi Chen, Bárbara Cádiz, Lan Wang, François Paquet-Durand, Oliver Schmachtenberg.

  Müller cells, the glial cells of the retina, provide metabolic support for photoreceptors and inner retinal neurons, and have been proposed as source of the significant lactate production of this tissue. To better understand the role of lactate in retinal metabolism, we expressed a lactate and a glucose nanosensor in organotypic mouse retinal explants cultured for 14 days, and used FRET imaging in acute vibratome sections of the explants to study metabolite flux in real time. Pharmacological manipulation with specific monocarboxylate transporter (MCT) inhibitors and immunohistochemistry revealed the functional expression of MCT1, MCT2 and MCT4 in Müller cells of retinal explants. The introduction of FRET nanosensors to measure key metabolites at the cellular level may contribute to a better understanding of heretofore poorly understood issues in retinal metabolism.

Keywords:  Diabetic retinopathy; Lactate; Metabolism; Monocarboxylate transporters; Müller cells; Retina

DOI:  https://doi.org/10.1016/j.exer.2022.109352
Metabolites. 2022 Dec 16. pii: 1280. [Epub ahead of print]12(12):

Lipid Alterations in Glioma: A Systematic Review.

Khairunnisa Abdul Rashid, Kamariah Ibrahim, Jeannie Hsiu Ding Wong, Norlisah Mohd Ramli.

  Gliomas are highly lethal tumours characterised by heterogeneous molecular features, producing various metabolic phenotypes leading to therapeutic resistance. Lipid metabolism reprogramming is predominant and has contributed to the metabolic plasticity in glioma. This systematic review aims to discover lipids alteration and their biological roles in glioma and the identification of potential lipids biomarker. This systematic review was conducted using the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Extensive research articles search for the last 10 years, from 2011 to 2021, were conducted using four electronic databases, including PubMed, Web of Science, CINAHL and ScienceDirect. A total of 158 research articles were included in this study. All studies reported significant lipid alteration between glioma and control groups, impacting glioma cell growth, proliferation, drug resistance, patients' survival and metastasis. Different lipids demonstrated different biological roles, either beneficial or detrimental effects on glioma. Notably, prostaglandin (PGE2), triacylglycerol (TG), phosphatidylcholine (PC), and sphingosine-1-phosphate play significant roles in glioma development. Conversely, the most prominent anti-carcinogenic lipids include docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and vitamin D3 have been reported to have detrimental effects on glioma cells. Furthermore, high lipid signals were detected at 0.9 and 1.3 ppm in high-grade glioma relative to low-grade glioma. This evidence shows that lipid metabolisms were significantly dysregulated in glioma. Concurrent with this knowledge, the discovery of specific lipid classes altered in glioma will accelerate the development of potential lipid biomarkers and enhance future glioma therapeutics.

Keywords:  bioactive lipid compounds; glioma; lipid biomarker; lipid signals; lipids

DOI:  https://doi.org/10.3390/metabo12121280
J Inherit Metab Dis. 2022 Dec 23.

Pathogenic variants of the coenzyme A biosynthesis-associated enzyme phosphopantothenoylcysteine decarboxylase (PPCDC) cause autosomal-recessive dilated cardiomyopathy.

Irene Bravo-Alonso, Matías Morin, Laura Arribas-Carreira, Mar Álvarez, Consuelo Pedrón-Giner, Lucia Soletto, Carlos Santolaria, Santiago Ramón-Maiques, Magdalena Ugarte, Pilar Rodríguez-Pombo, Joaquín Ariño, Miguel Ángel Moreno-Pelayo, Belén Pérez.

  Coenzyme A (CoA) is an essential cofactor involved in a range of metabolic pathways including the activation of long-chain fatty acids for catabolism. Cells synthesize CoA de novo from vitamin B5 (pantothenate) via a pathway strongly conserved across prokaryotes and eukaryotes. In humans, it involves five enzymatic steps catalyzed by four enzymes: pantothenate kinase (PANK [isoforms 1-4]), 4'-phosphopantothenoylcysteine synthetase (PPCS), phosphopantothenoylcysteine decarboxylase (PPCDC), and CoA synthase (COASY). To date, inborn errors of metabolism associated with all of these genes, except PPCDC, have been described, two related to neurodegeneration with brain iron accumulation (NBIA), and one associated with a cardiac phenotype. This paper reports another defect in this pathway (detected in two sisters), associated with a fatal cardiac phenotype, caused by biallelic variants (p.Thr53Pro and p.Ala95Val) of PPCDC. PPCDC enzyme (EC 4.1.1.36) catalyzes the decarboxylation of 4'-phosphopantothenoylcysteine to 4'-phosphopantetheine in CoA biosynthesis. The variants p.Thr53Pro and p.Ala95Val affect residues highly conserved across different species; p.Thr53Pro is involved in the binding of flavin mononucleotide, and p.Ala95Val is likely a destabilizing mutation. Patient-derived fibroblasts showed an absence of PPCDC protein, and nearly 50% reductions in CoA levels. The cells showed clear energy deficiency problems, with defects in mitochondrial respiration, , and mostly glycolytic ATP synthesis. Functional studies performed in yeast suggest these mutations to be functionally relevant. In summary, this work describes a new, ultra-rare, severe inborn error of metabolism due to pathogenic variants of PPCDC.

Keywords:  Biosynthesis of coenzyme A; PPCDC; dilated cardiomyopathy; inborn errors of metabolism

DOI:  https://doi.org/10.1002/jimd.12584
Physiol Rep. 2022 Dec;10(24): e15542

Effects of aging and long-term physical activity on mitochondrial physiology and redox state of the cortex and cerebellum of female rats.

Paulo H C Mesquita, Shelby C Osburn, Joshua S Godwin, Michael D Roberts, Andreas N Kavazis.

  We investigated the effects of aging and long-term physical activity on markers of mitochondrial function and dynamics in the cortex and cerebellum of female rats. Additionally, we interrogated markers of oxidative damage and antioxidants. Thirty-four female Lewis rats were separated into three groups. A young group (YNG, n = 10) was euthanized at 6 months of age. Two other groups were aged to 15 months and included a physical activity group (MA-PA, n = 12) and a sedentary group (MA-SED, n = 12). There were no age effects for any of the variables investigated, except for SOD2 protein levels in the cortex (+6.5%, p = 0.012). Long-term physical activity increased mitochondrial complex IV activity in the cortex compared to YNG (+85%, p = 0.016) and MA-SED (+82%, p = 0.023) and decreased carbonyl levels in the cortex compared to YNG (-12.49%, p = 0.034). Our results suggest that the mitochondrial network and redox state of the brain of females may be more resilient to the aging process than initially thought. Further, voluntary wheel running had minimal beneficial effects on brain markers of oxidative damage and mitochondrial physiology.

Keywords:  antioxidants; brain; exercise; mitochondrial dynamics; mitochondrial function; oxidative damage

DOI:  https://doi.org/10.14814/phy2.15542
Brain Sci. 2022 Dec 15. pii: 1718. [Epub ahead of print]12(12):

Role for Astrocytes in mGluR-Dependent LTD in the Neocortex and Hippocampus.

Ulyana Lalo, Yuriy Pankratov.

  Astroglia are an active element of brain plasticity, capable to release small molecule gliotransmitters by various mechanisms and regulate synaptic strength. While importance of glia-neuron communications for long-term potentiation has been rather widely reported, research into role for astrocytes in long-depression (LTD) is just gaining momentum. Here, we explored the role for astrocytes in the prominent form of synaptic plasticity-mGluR-dependent LTD. We found out the substantial contribution of the Group I receptors, especially mGluR1 subtype, into Ca2+-signaling in hippocampal and neocortical astrocytes, which can be activated during synaptic stimulation used for LTD induction. Our data demonstrate that mGluR receptors can activate SNARE-dependent release of ATP from astrocytes which in turn can directly activate postsynaptic P2X receptors in the hippocampal and neocortical neurons. The latter mechanism has recently been shown to cause the synaptic depression via triggering the internalisation of AMPA receptors. Using mouse model of impaired glial exocytosis (dnSNARE mice), we demonstrated that mGluR-activated release of ATP from astrocytes is essential for regulation of mGluR-dependent LTD in CA3-CA1 and layer 2/3 synapses. Our data also suggest that astrocyte-related pathway relies mainly on mGluR1 receptors and act synergistically with neuronal mechanisms dependent mainly on mGluR5.

Keywords:  AMPA internalisation; AMPA receptors; Ca2+ microdomain; LTD; P2X receptors; glia-neuron interactions; synaptic strength

DOI:  https://doi.org/10.3390/brainsci12121718
Biomedicines. 2022 Dec 07. pii: 3171. [Epub ahead of print]10(12):

A Missense Variant in PDK1 Associated with Severe Neurodevelopmental Delay and Epilepsy.

Raquel Vaz, Josephine Wincent, Najla Elfissi, Kristina Rosengren Forsblad, Maria Pettersson, Karin Naess, Anna Wedell, Anna Wredenberg, Anna Lindstrand, Sofia Ygberg.

  The pyruvate dehydrogenase complex (PDC) is responsible for the conversion of pyruvate into acetyl-CoA, which is used for energy conversion in cells. PDC activity is regulated by phosphorylation via kinases and phosphatases (PDK/PDP). Variants in all subunits of the PDC and in PDK3 have been reported, with varying phenotypes including lactic acidosis, neurodevelopmental delay, peripheral neuropathy, or seizures. Here, we report a de novo heterozygous missense variant in PDK1 (c.1139G > A; p.G380D) in a girl with developmental delay and early onset severe epilepsy. To investigate the role of PDK1G380D in energy metabolism and neuronal development, we used a zebrafish model. In zebrafish embryos we show a reduced number of cells with mitochondria with membrane potential, reduced movements, and a delay in neuronal development. Furthermore, we observe a reduction in the phosphorylation of PDH-E1α by PDKG380D, which suggests a disruption in the regulation of PDC activity. Finally, in patient fibroblasts, a mild reduction in the ratio of phosphorylated PDH over total PDH-E1α was detected. In summary, our findings support the notion that this aberrant PDK1 activity is the cause of clinical symptoms in the patient.

Keywords:  epilepsy; neurodevelopmental delay; pyruvate dehydrogenase kinase; zebrafish

DOI:  https://doi.org/10.3390/biomedicines10123171
Front Aging Neurosci. 2022 ;14 1075161

Effect of β-hydroxybutyrate on behavioral alterations, molecular and morphological changes in CNS of multiple sclerosis mouse model.

Wei Sun, Min Wen, Min Liu, Qingpeng Wang, Quiqin Liu, Lanjie Li, Hans-Christian Siebert, Gabriele Loers, Ruiyan Zhang, Ning Zhang.

  Multiple sclerosis (MS) is a chronic inflammatory and degenerative disease of central nervous system (CNS). Aging is the most significant risk factor for the progression of MS. Dietary modulation (such as ketogenic diet) and caloric restriction, can increase ketone bodies, especially β-hydroxybutyrate (BHB). Increased BHB has been reported to prevent or improve age-related disease. The present studies were performed to understand the therapeutic effect and potential mechanisms of exogenous BHB in cuprizone (CPZ)-induced demyelinating model. In this study, a continuous 35 days CPZ mouse model with or without BHB was established. The changes of behavior function, pathological hallmarks of CPZ, and intracellular signal pathways in mice were detected by Open feld test, Morris water maze, RT-PCR, immuno-histochemistry, and western blot. The results showed that BHB treatment improved behavioral performance, prevented myelin loss, decreased the activation of astrocyte as well as microglia, and up-regulated the neurotrophin brain-derived neurotrophic factor in both the corpus callosum and hippocampus. Meanwhile, BHB treatment increased the number of MCT1+ cells and APC+ oligodendrocytes. Furthermore, the treatment decreased the expression of HDAC3, PARP1, AIF and TRPA1 which is related to oligodendrocyte (OL) apoptosis in the corpus callosum, accompanied by increased expression of TrkB. This leads to an increased density of doublecortin (DCX)+ neuronal precursor cells and mature NeuN+ neuronal cells in the hippocampus. As a result, BHB treatment effectively promotes the generation of PDGF-Ra+ (oligodendrocyte precursor cells, OPCs), Sox2+ cells and GFAP+ (astrocytes), and decreased the production of GFAP+ TRAP1+ cells, and Oligo2+ TRAP1+ cells in the corpus callosum of mouse brain. Thus, our results demonstrate that BHB treatment efficiently supports OPC differentiation and decreases the OLs apoptosis in CPZ-intoxicated mice, partly by down-regulating the expression of TRPA1 and PARP, which is associated with the inhibition of the p38-MAPK/JNK/JUN pathway and the activation of ERK1/2, PI3K/AKT/mTOR signaling, supporting BHB treatment adjunctive nutritional therapy for the treatment of chronic demyelinating diseases, such as multiple sclerosis (MS).

Keywords:  PARP; TRPA1; demyelination; multiple sclerosis; β-hydroxybutyrate

DOI:  https://doi.org/10.3389/fnagi.2022.1075161
Nat Commun. 2022 Dec 21. 13(1): 7791

Huntington disease oligodendrocyte maturation deficits revealed by single-nucleus RNAseq are rescued by thiamine-biotin supplementation.

Ryan G Lim, Osama Al-Dalahmah, Jie Wu, Maxwell P Gold, Jack C Reidling, Guomei Tang, Miriam Adam, David K Dansu, Hye-Jin Park, Patrizia Casaccia, Ricardo Miramontes, Andrea M Reyes-Ortiz, Alice Lau, Richard A Hickman, Fatima Khan, Fahad Paryani, Alice Tang, Kenneth Ofori, Emily Miyoshi, Neethu Michael, Nicolette McClure, Xena E Flowers, Jean Paul Vonsattel, Shawn Davidson, Vilas Menon, Vivek Swarup, Ernest Fraenkel, James E Goldman, Leslie M Thompson.

The complexity of affected brain regions and cell types is a challenge for Huntington's disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identify PRKCE and Thiamine Pyrophosphokinase 1 (TPK1) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1 dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism.

DOI: https://doi.org/10.1038/s41467-022-35388-x
Biochem Biophys Res Commun. 2022 Dec 13. pii: S0006-291X(22)01702-8. [Epub ahead of print]641 186-191

Endogenous d-serine exists in the mammalian brain independent of synthesis by serine racemase.

Akina Osaki, Marie Aoyama, Masashi Mita, Kenji Hamase, Masato Yasui, Jumpei Sasabe.

  Activation of N-methyl-d-aspartate receptors (NMDARs) requires binding of a co-agonist in addition to l-glutamate. d-serine binds to the co-agonist site on GluN1 subunits of NMDARs and modulates glutamatergic neurotransmission. While loss of GluN1 subunits in mice results in neonatal death due to respiratory failure, animals that lack a d-serine synthetic enzyme, serine racemase (SR), show grossly normal growth. However, SR-independent origins of d-serine in the brain remain unclarified. In the present study, we investigated the origin of brain d-serine in mice. Loss of SR significantly reduced d-serine in the cerebral cortex, but a portion of d-serine remained in both neonates and adults. Although d-serine was also produced by intestinal bacteria, germ-free experiments did not influence d-serine levels in the cerebral cortex. In addition, treatment of SR-knockout mice with antibiotics showed a significant reduction of intestinal d-serine, but no reduction in the brain. On the other hand, restriction of dietary intake reduced systemic circulation of d-serine and resulted in a slight decrease of d-serine in the cerebral cortex, but did not account for brain d-serine found in the SR-knockout mice. Therefore, our findings show that endogenous d-serine of non-SR origin exists in the brain. Such previously unrecognized, SR-independent, endogenous d-serine may contribute baseline activity of NMDARs, especially in developing brain, which has minimal SR expression.

Keywords:  (d)(-)serine; And (d)(-)amino acids; GluN1; NMDAR; Serine racemase

DOI:  https://doi.org/10.1016/j.bbrc.2022.12.037
Mov Disord. 2022 Dec 21.

Reduced D2 /D3 Receptor Binding and Glucose Metabolism in a Macaque Model of Huntington's Disease.

Alison R Weiss, Daniele Bertoglio, William A Liguore, Kristin Brandon, John Templon, Jeanne Link, Jodi L McBride.

   BACKGROUND: Dopamine system dysfunction and altered glucose metabolism are implicated in Huntington's disease (HD), a neurological disease caused by mutant huntingtin (mHTT) expression.
OBJECTIVE: The aim was to characterize alterations in cerebral dopamine D2 /D3 receptor density and glucose utilization in a newly developed AAV-mediated NHP model of HD that expresses mHTT throughout numerous brain regions.
METHODS: Positron emission tomography (PET) imaging was performed using [18 F]fallypride to quantify D2 /D3 receptor density and 2-[18 F]fluoro-2-deoxy-d-glucose ([18 F]FDG) to measure cerebral glucose utilization in these HD macaques.
RESULTS: Compared to controls, HD macaques showed significantly reduced dopamine D2 /D3 receptor densities in basal ganglia (P < 0.05). In addition, HD macaques displayed significant glucose hypometabolism throughout the cortico-basal ganglia network (P < 0.05).
CONCLUSIONS: [18 F]Fallypride and [18 F]FDG are PET imaging biomarkers of mHTT-mediated disease progression that can be used as noninvasive outcome measures in future therapeutic studies with this AAV-mediated HD macaque model. © 2022 International Parkinson and Movement Disorder Society.

Keywords:  2-[18F]fluoro-2-deoxy-d-glucose; binding potential; cortical-basal ganglia; fallypride; positron emission tomography imaging

DOI:  https://doi.org/10.1002/mds.29271
Int J Mol Sci. 2022 Dec 19. pii: 16175. [Epub ahead of print]23(24):

N-Acetylcysteine Administration Attenuates Sensorimotor Impairments Following Neonatal Hypoxic-Ischemic Brain Injury in Rats.

Evangelia Kesidou, Christina Bitsina, Athanasios Chatzisotiriou, Paschalis Theotokis, Evgenia Dandi, Despina A Tata, Evangelia Spandou.

  Hypoxic ischemic (HI) brain injury that occurs during neonatal period has been correlated with severe neuronal damage, behavioral deficits and infant mortality. Previous evidence indicates that N-acetylcysteine (NAC), a compound with antioxidant action, exerts a potential neuroprotective effect in various neurological disorders including injury induced by brain ischemia. The aim of the present study was to investigate the role of NAC as a potential therapeutic agent in a rat model of neonatal HI brain injury and explore its long-term behavioral effects. To this end, NAC (50 mg/kg/dose, i.p.) was administered prior to and instantly after HI, in order to evaluate hippocampal and cerebral cortex damage as well as long-term functional outcome. Immunohistochemistry was used to detect inducible nitric oxide synthase (iNOS) expression. The results revealed that NAC significantly alleviated sensorimotor deficits and this effect was maintained up to adulthood. These improvements in functional outcome were associated with a significant decrease in the severity of brain damage. Moreover, NAC decreased the short-term expression of iNOS, a finding implying that iNOS activity may be suppressed and that through this action NAC may exert its therapeutic action against neonatal HI brain injury.

Keywords:  N-acetylcysteine (NAC); brain injury; hypoxia; inducible nitric oxide synthase (iNOS); ischemia; neuroprotection; sensorimotor tests

DOI:  https://doi.org/10.3390/ijms232416175
Ann Neurol. 2022 Dec 22.

APOE2 Exacerbates TDP-43 Related Toxicity in the Absence of Alzheimer Pathology.

Axel D Meneses, Shunsuke Koga, Zonghua Li, Justin O'Leary, Fuyao Li, Kai Chen, Aya Murakami, Wenhui Qiao, Aishe Kurti, Michael G Heckman, Launia White, Manling Xie, Yixing Chen, NiCole A Finch, Melina J Lim, Marion Delenclos, Michael A DeTure, Cynthia Linares, Nicholas B Martin, Tadafumi C Ikezu, Marka M van Blitterswijk, Long-Jun Wu, Pamela J McLean, Rosa Rademakers, Owen A Ross, Dennis W Dickson, Guojun Bu, Na Zhao.

OBJECTIVE: Recent evidence supports a link between increased TDP-43 burden and the presence of an APOE4 gene allele in Alzheimer's disease (AD); however, it is difficult to conclude the direct effect of APOE on TDP-43 pathology due to the presence of mixed AD pathologies. The goal of this study is to address how APOE isoforms impact TDP-43 pathology and related neurodegeneration in the absence of typical AD pathologies.
METHODS: We overexpressed human TDP-43 via viral transduction in humanized APOE2, APOE3, APOE4 mice, and murine Apoe-knockout (Apoe-KO) mice. Behavior tests were performed across ages. Animals were harvested at 11 months of age and TDP-43 overexpression-related neurodegeneration and gliosis were assessed. To further address the human relevance, we analyzed the association of APOE with TDP-43 pathology in 160 postmortem brains from autopsy-confirmed amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with motor neuron disease (FTLD-MND) in the Mayo Clinic Brain Bank.
RESULTS: We found that TDP-43 overexpression induced motor function deficits, neuronal loss, and gliosis in the motor cortex, especially in APOE2 mice, with much milder or absent effects in APOE3, APOE4, or Apoe-KO mice. In the motor cortex of the ALS and FTLD-MND postmortem human brains, we found that the APOE2 allele was associated with more severe TDP-43-positive dystrophic neurites.
INTERPRETATION: Our data suggest a genotype-specific effect of APOE on TDP-43 proteinopathy and neurodegeneration in the absence of AD pathology, with the strongest association seen with APOE2. This article is protected by copyright. All rights reserved.

DOI: https://doi.org/10.1002/ana.26580
Int Immunopharmacol. 2022 Dec 15. pii: S1567-5769(22)01029-3. [Epub ahead of print]114 109544

Amelioration of central neurodegeneration by docosahexaenoic acid in trigeminal neuralgia rats through the regulation of central neuroinflammation.

Guo Mu, Changhe Ren, Yue Zhang, Bin Lu, Jianguo Feng, Dan Wu, Xinxin Xu, Cehua Ou.

  Trigeminal neuralgia (TN) is a stubborn head and face neuropathic pain with complex pathogenesis. Patients with TN have a significantly increased risk of central neurodegeneration, which manifests as cognitive impairment and memory loss, but the specific mechanism underlying central nervous degeneration is still unclear. This study aimed to explore central neurodegeneration and its possible mechanism of action in TN rats based on changes in the brain fatty acid content and microglia-related neuroinflammation. Using a TN neuropathic pain model established by us, we found that TN rats have obvious cognitive impairment. Furthermore, changes in the brain fatty acid content were analyzed using gas chromatography-mass spectrometry (GC-MS). It was found that the docosahexaenoic acid (DHA) content in the central nervous system (CNS) of TN rats was significantly decreased compared to that in the CNS of Sham rats. An important component in maintaining brain cognition, DHA also plays a key role in regulating central neuroinflammation. Here, by continuous supplementation of DHA, the CNS DHA content was increased to a certain extent in TN rats. The cognitive impairment of TN rats was improved after restoring the central DHA level; this may be related to the improvement of neuroinflammation through the DHA-mediated regulation of microglial polarization. Overall, this study provides a theoretical basis for explaining the pathogenesis of central neurodegeneration in TN. It also suggests DHA as a target for protecting the CNS of patients with TN from damage.

Keywords:  Cognitive impairment; Docosahexaenoic acid; Inflammation; Microglia; Neurodegeneration; Trigeminal neuralgia

DOI:  https://doi.org/10.1016/j.intimp.2022.109544
Curr Opin Neurobiol. 2022 Dec 16. pii: S0959-4388(22)00158-1. [Epub ahead of print]78 102664

Mitochondrial signaling on innate immunity activation in Parkinson disease.

João D Magalhães, Sandra Morais Cardoso.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the accumulation of alpha-synuclein (aSyn) in the nigrostriatal pathway that is followed by severe neuroinflammatory response. PD etiology is still puzzling; however, the mitocentric view might explain the vast majority of molecular findings not only in the brain, but also at systemic level. While neuronal degeneration is tightly associated with mitochondrial dysfunction, the causal role between aSyn accumulation and mitochondrial dysfunction still requires further investigation. Moreover, mitochondrial dysfunction can elicit an inflammatory response that may be transmitted locally but also in a long range through systemic circulation. Furthermore, mitochondrial-driven innate immune activation may involve the synthesis of antimicrobial peptides, of which aSyn poses as a good candidate. While there is still a need to clarify disease-elicited mechanisms and how aSyn has the ability to modulate mitochondrial and cellular dysfunction, recent studies provide insightful views on mitochondria-inflammation axis in PD etiology.

DOI: https://doi.org/10.1016/j.conb.2022.102664
BMJ Case Rep. 2022 Dec 19. pii: e251321. [Epub ahead of print]15(12):

Do renal and cardiac malformations in the fetus signal carnitine palmitoyltransferase II deficiency? A rare lethal fatty acid oxidation defect.

Yee Yin Tan, Wen Yan Nikki Fong, Charmaine Jiahui Chan, Suresh Chandran.

  The neonatal form of carnitine palmitoyltransferase II (CPT II) deficiency is a rare lethal inherited disorder of fatty acid oxidation. Carnitine essentially transfers long-chain fatty acids across the mitochondrial membranes for β-oxidation, where CPT II plays a key role. CPT II deficiency phenotypical forms include lethal neonatal, severe infantile and myopathic forms. We present a term small-for-gestational-age neonate with hypoglycaemia, seizures, refractory cardiac arrhythmias and intracranial haemorrhage. Plasma acylcarnitine profile and the genetic study confirmed CPT II deficiency. Additionally, likely pathogenic variants in the SLC22A5 gene point to primary carnitine deficiency. Antenatal findings of polycystic kidney disease and cardiomegaly were confirmed postnatally. All supportive measures, including extracorporeal life support, failed to improve the clinical course, and the baby succumbed. Major renal, cerebral and cardiac anomalies were reported with CPT II deficiency. In our case, fetal polycystic nephromegaly and cardiomegaly with parental consanguinity should have signalled the possibility of this disorder.

Keywords:  Arrhythmias; Congenital disorders; Neonatal intensive care

DOI:  https://doi.org/10.1136/bcr-2022-251321
PLoS Comput Biol. 2022 Dec 21. 18(12): e1010739

A method to estimate the cellular composition of the mouse brain from heterogeneous datasets.

Dimitri Rodarie, Csaba Verasztó, Yann Roussel, Michael Reimann, Daniel Keller, Srikanth Ramaswamy, Henry Markram, Marc-Oliver Gewaltig.

The mouse brain contains a rich diversity of inhibitory neuron types that have been characterized by their patterns of gene expression. However, it is still unclear how these cell types are distributed across the mouse brain. We developed a computational method to estimate the densities of different inhibitory neuron types across the mouse brain. Our method allows the unbiased integration of diverse and disparate datasets into one framework to predict inhibitory neuron densities for uncharted brain regions. We constrained our estimates based on previously computed brain-wide neuron densities, gene expression data from in situ hybridization image stacks together with a wide range of values reported in the literature. Using constrained optimization, we derived coherent estimates of cell densities for the different inhibitory neuron types. We estimate that 20.3% of all neurons in the mouse brain are inhibitory. Among all inhibitory neurons, 18% predominantly express parvalbumin (PV), 16% express somatostatin (SST), 3% express vasoactive intestinal peptide (VIP), and the remainder 63% belong to the residual GABAergic population. We find that our density estimations improve as more literature values are integrated. Our pipeline is extensible, allowing new cell types or data to be integrated as they become available. The data, algorithms, software, and results of our pipeline are publicly available and update the Blue Brain Cell Atlas. This work therefore leverages the research community to collectively converge on the numbers of each cell type in each brain region.

DOI: https://doi.org/10.1371/journal.pcbi.1010739
Molecules. 2022 Dec 09. pii: 8754. [Epub ahead of print]27(24):

Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases.

Sifan Wang, Yuanbo Kang, Ruifeng Wang, Junqi Deng, Yupei Yu, Jun Yu, Junpu Wang.

  NADH:ubiquinone oxidoreductase core subunit S8 (NDUFS8) is an essential core subunit and component of the iron-sulfur (FeS) fragment of mitochondrial complex I directly involved in the electron transfer process and energy metabolism. Pathogenic variants of the NDUFS8 are relevant to infantile-onset and severe diseases, including Leigh syndrome, cancer, and diabetes mellitus. With over 1000 nuclear genes potentially causing a mitochondrial disorder, the current diagnostic approach requires targeted molecular analysis, guided by a combination of clinical and biochemical features. Currently, there are only several studies on pathogenic variants of the NDUFS8 in Leigh syndrome, and a lack of literature on its precise mechanism in cancer and diabetes mellitus exists. Therefore, NDUFS8-related diseases should be extensively explored and precisely diagnosed at the molecular level with the application of next-generation sequencing technologies. A more distinct comprehension will be needed to shed light on NDUFS8 and its related diseases for further research. In this review, a comprehensive summary of the current knowledge about NDUFS8 structural function, its pathogenic mutations in Leigh syndrome, as well as its underlying roles in cancer and diabetes mellitus is provided, offering potential pathogenesis, progress, and therapeutic target of different diseases. We also put forward some problems and solutions for the following investigations.

Keywords:  Leigh syndrome; NDUFS8; cancer; diabetes mellitus; metabolism; mitochondrial complex I

DOI:  https://doi.org/10.3390/molecules27248754
Nat Metab. 2022 Dec;4(12): 1756-1774

Dual roles of hexokinase 2 in shaping microglial function by gating glycolytic flux and mitochondrial activity.

Yaling Hu, Kelei Cao, Fang Wang, Weiying Wu, Weihao Mai, Liyao Qiu, Yuxiang Luo, Woo-Ping Ge, Binggui Sun, Ligen Shi, Junming Zhu, Jianmin Zhang, Zhiying Wu, Yicheng Xie, Shumin Duan, Zhihua Gao.

Microglia continuously survey the brain parenchyma and actively shift status following stimulation. These processes demand a unique bioenergetic programme; however, little is known about the metabolic determinants in microglia. By mining large datasets and generating transgenic tools, here we show that hexokinase 2 (HK2), the most active isozyme associated with mitochondrial membrane, is selectively expressed in microglia in the brain. Genetic ablation of HK2 reduced microglial glycolytic flux and energy production, suppressed microglial repopulation, and attenuated microglial surveillance and damage-triggered migration in male mice. HK2 elevation is prominent in immune-challenged or disease-associated microglia. In ischaemic stroke models, however, HK2 deletion promoted neuroinflammation and potentiated cerebral damages. The enhanced inflammatory responses after HK2 ablation in microglia are associated with aberrant mitochondrial function and reactive oxygen species accumulation. Our study demonstrates that HK2 gates both glycolytic flux and mitochondrial activity to shape microglial functions, changes of which contribute to metabolic abnormalities and maladaptive inflammation in brain diseases.

DOI: https://doi.org/10.1038/s42255-022-00707-5