81 reads in the past 30 days
Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytesMarch 2023
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622 Reads
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53 Citations
Published by Wiley and International Society for Neurochemistry
Online ISSN: 1471-4159
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Print ISSN: 0022-3042
Disciplines: Neuroscience
81 reads in the past 30 days
Milestone Review: Metabolic dynamics of glutamate and GABA mediated neurotransmission — The essential roles of astrocytesMarch 2023
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622 Reads
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53 Citations
45 reads in the past 30 days
Prion Protein Endoproteolysis: Cleavage Sites, Mechanisms and Connections to Prion DiseaseJanuary 2025
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47 Reads
40 reads in the past 30 days
The role of serotonin in depression—A historical roundup and future directionsMarch 2024
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353 Reads
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11 Citations
37 reads in the past 30 days
Unsaturated Fatty Acids Are Decreased in Aβ Plaques in Alzheimer's DiseaseJanuary 2025
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37 Reads
35 reads in the past 30 days
(Re)building the nervous system: A review of neuron–glia interactions from development to diseaseDecember 2024
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162 Reads
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1 Citation
The Journal of Neurochemistry is dedicated to disseminating research covering all aspects of neurochemistry including molecular, cellular, biochemical and behavioural aspects of the nervous system, with a focus on pathogenesis, biomarkers and treatment of neurological and psychiatric disorders. We prioritize original research that demonstrates a mechanistic advance as well as critical reviews that highlight progression of knowledge in the field. We are owned by the International Society for Neurochemistry.
February 2025
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2 Reads
Michael Lanz
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Maurizio Cortada
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Yu Lu
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Daniel Bodmer
Mammalian target of rapamycin complex 2 (mTORC2) is essential for hearing by regulating auditory hair cell structure and function. However, mechanistic details of how mTORC2 regulates intracellular processes in sensory hair cells have not yet been clarified. To further elucidate the role of mTORC2 in auditory cells, we generated a Rictor knockout cell line from HEI‐OC1 auditory cells. mTORC2‐deficient auditory cells exhibited significant alterations in actin cytoskeleton morphology and decreased proliferation rates. Additionally, we observed a reduction in phosphorylation of protein kinase C alpha (PKCα) and disrupted actin polymerization in mTORC2‐deficient cells. Using proteomics, we found that mTORC2 disruption altered expression of cytoskeleton‐related proteins in auditory cells. These findings provide valuable mechanistic insights into the functional role of mTORC2 in auditory cells, potentially opening new perspectives to address sensorineural hearing loss. image
February 2025
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4 Reads
Juan Ji
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Ye‐Fan Chen
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Chen Hong
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[...]
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Xiu‐Lan Sun
Oxidative stress‐mediated astrocytic damage contributes to nerve injury and the development of depression, especially under stress conditions. Peroxisomes and pexophagy are essential for balancing oxidative stress and protein degradation products. Our previous findings suggest that peroxisome proliferators‐activated receptor β/δ (PPARβ/δ) activation significantly alleviates depressive behaviors by preventing astrocytic injury. However, the underlying mechanisms remain unclear. In the present study, we established oxidative injury by treating astrocytes with corticosterone. Subsequently, PPARβ/δ agonists and antagonists were applied to determine the effects of PPARβ/δ on balancing peroxisomes and pexophagy in astrocytes. The PPARβ/δ agonist (GW0742) significantly improved cell viability and decreased intracellular reactive oxygen species (ROS) production induced by corticosterone, while pretreatment with the PPARβ/δ, antagonist GSK3787 reversed the effects of GW0742. Moreover, activating PPARβ/δ promoted peroxisomal biogenesis factor 5 (PEX5)‐mediated pexophagy by enhancing the phosphorylation of ataxia‐telangiectasia mutated (ATM) kinase. Conversely, blocking PPARβ/δ with GSK3787 partially abolished the effects of GW0742. Further investigations demonstrated that activation of PPARβ/δ not only induced transcription of the ubiquitin protein ligase E3 component n‐recognin 5 (UBR5) but also enhanced the interaction between PPARβ/δ and UBR5, contributing to ATM interactor (ATMIN) degradation, and increased phosphorylated ATM kinase levels. Therefore, this study revealed that activating PPARβ/δ improves corticosterone‐induced oxidative damage in astrocytes by enhancing pexophagy. PPARβ/δ directly interacts with UBR5 to facilitate ATMIN degradation and promotes ATM phosphorylation, thereby maintaining the balance between peroxisomes and pexophagy. These findings suggest that PPARβ/δ is a potential target for promoting pexophagy in astrocytes upon stress. image
February 2025
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10 Reads
Marilyn C. Cornelis
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Amir Fazlollahi
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David A. Bennett
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Scott Ayton
Brain iron (Fe) dyshomeostasis is implicated in neurodegenerative diseases. Genome‐wide association studies (GWAS) have identified plausible loci correlated with peripheral levels of Fe. Systemic organs and the brain share several Fe regulatory proteins but there likely exist different homeostatic pathways. We performed the first GWAS of inductively coupled plasma mass spectrometry measures of postmortem brain Fe from 635 Rush Memory and Aging Project (MAP) participants. Sixteen single nucleotide polymorphisms (SNPs) associated with Fe in at least one of four brain regions were measured (p < 5 × 10⁻⁸). Promising SNPs (p < 5 × 10⁻⁶) were followed up for replication in published GWAS of blood, spleen, and brain imaging Fe traits and mapped to candidate genes for targeted cortical transcriptomic and epigenetic analysis of postmortem Fe in MAP. Results for SNPs previously associated with other Fe traits were also examined. Ninety‐eight SNPs associated with postmortem brain Fe were at least nominally (p < 0.05) associated with one or more related Fe traits. Most novel loci identified had no direct links to Fe regulatory pathways but rather endoplasmic reticulum‐Golgi trafficking (SORL1, SORCS2, MARCH1, CLTC), heparan sulfate (HS3ST4, HS3ST1), and coenzyme A (SLC5A6, PANK3); supported by nearest gene function and omic analyses. We replicated (p < 0.05) several previously published Fe loci mapping to candidate genes in cellular and systemic Fe regulation. Finally, novel loci (BMAL, COQ5, SLC25A11) and replication of prior loci (PINK1, PPIF, LONP1) lend support to the role of circadian rhythms and mitochondria function in Fe regulation more generally. In summary, we provide support for novel loci linked to pathways that may have greater relevance to brain Fe accumulation; some of which are implicated in neurodegeneration. However, replication of a subset of prior loci for blood Fe suggests that genetic determinants or biological pathways underlying Fe accumulation in the brain are not completely distinct from those of Fe circulating in the periphery. image
February 2025
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2 Reads
Paula Silva Lacerda Almeida
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Dayana Araújo
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Juliana Minardi Nascimento
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Joice Stipursky
Consumption of alcoholic beverages during pregnancy is directly related to the establishment of fetal alcohol spectrum disorders (FASD), which includes craniofacial changes, body growth restriction, and neurodevelopment impairments. Proper functioning of the central nervous system (CNS) depends on blood–brain barrier (BBB) development, which is formed by interactions of vascular endothelial cells, pericytes, astrocytes, and basal lamina. Gestational exposure to ethanol has been demonstrated to impair CNS development; however, little is known about ethanol modulation of blood circulating factors and impacts on human developing BBB. Here we investigated the prevalence of alcohol consumption during pregnancy and found that 27% of pregnant women reported alcohol consumption, mainly in the first trimester. Control and alcohol‐exposed newborns showed no differences in weight, length, and appearance, pulse, grimace, activity, respiration (APGAR) score at birth. In vitro, we cultivated human brain microcapillary endothelial cells (HBMEC) and treated with umbilical cord blood serum (UCBS) from control (S‐Control) newborns or ethanol‐exposed ones (S‐Ethanol). S‐Ethanol treatment induced 68% and 38% decreases in protein levels of ZO‐1 (tight junction) and GLUT‐1 (glucose transporter type‐1), respectively, increased endothelial monolayer permeability, migratory potential impairment, and changes in angiogenesis‐related secreted proteins profile, compared to S‐Control treatments. UCBS proteomics revealed a total of 392 proteins, 10 exclusively found in S‐Ethanol, mostly related to innate and adaptive immunity and tissue injury response. These results suggest that gestational exposure to ethanol contributes to blood altered protein profiles triggering BBB endothelial. image
February 2025
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2 Reads
Sortilin‐related receptor 1 (SORL1) is a risk gene of Alzheimer's disease (AD), and some protein‐truncating (PTV) and rare missense variants causing the loss of function of SORL1 contribute to AD pathogenesis. SORL1 is an endosomal receptor that interacts with multiple protein sorting complexes to facilitate the transport of various cargoes through the endolysosomal network (ELN). However, the regulatory mechanisms governing SORL1 expression remain unknown. Through biochemical methods, we identified Forkhead Box P1 (FOXP1) as a binding protein to the minimal promoter region of SORL1 gene. Silencing FOXP1 using siRNA significantly decreased the activity of the SORL1 minimal promoter and reduced SORL1 protein and mRNA levels in the neuroblastoma cell line SH‐SY5Y. Additionally, using 5xFAD mouse models of AD, we observed significantly decreased FOXP1 and SORL1 expression in neurons within the prefrontal cortex. Disruption of ELN and the autophagy degradation system by bafilomycin A1 (BafA1) appeared to be a specific condition to suppress FOXP1 and hence SORL1 in SH‐SY5Y cells. These findings highlight the critical role of FOXP1 in regulating SORL1 expression and suggest that FOXP1 could be a potential target to maintain SORL1 expression for AD prevention and therapy. image
February 2025
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4 Reads
Sepsis‐associated encephalopathy (SAE) is a brain dysfunction for which no effective therapy currently exists. Recent studies suggest that transferring mitochondria from astrocytes to neurons may benefit SAE patients, though the underlying mechanism remains unclear. We cultured astrocytes and neurons from mice in vitro. Astrocytes were stimulated with lipopolysaccharide (LPS) for 24 h, and the astrocyte‐conditioned medium (ACM) was collected. Neuronal cultures were then treated with ACM or mitochondria‐depleted ACM (mdACM) for further analysis. Mitochondrial transfer was examined under a fluorescence microscope. Western blotting analyzed the protein expression of genes related to apoptosis and mitochondrial metabolism. RNA sequencing and mass spectrometry were employed to investigate the mechanisms underlying mitochondrial transfer. Astrocyte‐derived mitochondria migrated toward and connected with LPS‐exposed neurons. The addition of ACM significantly attenuated LPS‐induced alterations in the proteins linked to apoptosis and mitochondrial dynamics. RNA sequencing revealed notable alterations in the transcript profile of neurons upon ACM treatment, highlighting the involvement of mitochondria metabolism, inflammation, and apoptosis‐related factors. Additionally, mitochondrial transfer modified the lipid composition of neurons, increasing phosphatidylserine levels, which correlated with neuroinflammation and enriched pathways related to cytokine and MAPK signaling. Our findings suggest that astrocyte‐neuron mitochondrial transfer holds therapeutic potential for alleviating SAE, possibly through the anti‐inflammatory effects of lipids, particularly phosphatidylserine. image
February 2025
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5 Reads
Dopamine is a neurotransmitter that plays a significant role in reward and motivation. Dysfunction in the mesolimbic dopamine pathway has been linked to a variety of psychiatric disorders, including addiction. Low‐intensity focused ultrasound (LIFU) has demonstrated effects on brain activity, but how LIFU affects dopamine neurotransmission is not known. Here, we applied three different intensities (6.5, 13, and 26 W/cm² ISPPA) of 2‐min LIFU to the prelimbic cortex (PLC) and measured dopamine in the nucleus accumbens (NAc) core using fast‐scan cyclic voltammetry. Two minutes of LIFU sonication at 13 W/cm² to the PLC significantly reduced dopamine release by ~50% for up to 2 h. However, double the intensity (26 W/cm²) resulted in less inhibition (~30%), and half the intensity (6.5 W/cm²) did not result in any inhibition of dopamine. Anatomical controls applying LIFU to the primary somatosensory cortex did not change NAc core dopamine, and applying LIFU to the PLC did not affect dopamine release in the caudate or NAc shell. Histological evaluations showed no evidence of cell damage or death. Modeling temperature rise demonstrates a maximum temperature change of 0.5°C with 13 W/cm², suggesting that modulation is not due to thermal mechanisms. These studies show that LIFU at a moderate intensity provides a noninvasive, high spatial resolution means to modulate specific mesolimbic circuits that could be used in future studies to target and repair pathways that are dysfunctional in addiction and other psychiatric diseases. image
February 2025
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22 Reads
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Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive loss of midbrain dopaminergic neurons, leading to motor symptoms such as tremors, rigidity, and bradykinesia. Non‐motor symptoms, including depression, hyposmia, and sleep disturbances, often emerge in the early stages of PD, but their mechanisms remain poorly understood. The 6‐hydroxydopamine (6‐OHDA) rodent model is a well‐established tool for preclinical research, replicating key motor and non‐motor symptoms of PD. In this review, we systematically analyzed 135 studies that used 6‐OHDA rodent models of PD to investigate non‐motor symptoms. The review process adhered to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines. Our analysis highlights the growing use of 6‐OHDA PD models for experimental research of non‐motor symptoms. It also reveals significant variability in methodologies, including choices of brain target, toxin dosage, lesion verification strategies, and behavioral assessment reporting. Factors that hinder reproducibility and comparability of findings across studies. We highlight the need for standardization in 6‐OHDA‐based models with particular emphasis on consistent evaluation of lesion extent and reporting of the co‐occurrence of non‐motor symptoms. By fostering methodological coherence, this framework aims to enhance the reproducibility, reliability, and translational value of 6‐OHDA models in PD non‐motor symptom research. image
February 2025
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14 Reads
Synapse elimination is an essential process in the healthy nervous system and is dysregulated in many neuropathologies. Yet, the underlying molecular mechanisms and under what conditions they occur remain unclear. MFG‐E8 is a secreted glycoprotein well known to act as an opsonin, tagging stressed and dying cells for engulfment by phagocytes. Opsonization of cells and debris by MFG‐E8 for microglial phagocytosis in the CNS is well established, and its role in astrocytic phagocytosis, and trogocytosis‐like engulfment of synapses is beginning to be explored. However, MFG‐E8's function in other tissues is highly diverse, and evidence suggests that its role in the nervous system and on synapse elimination in particular may be more complex and varied than opsonization. In this review, we outline the documented direct and indirect effects of MFG‐E8 on synapse elimination, while also proposing potential roles to be explored further, in particular, cytoskeletal reorganization of neurites and glia leading to synapse elimination by various mechanisms. Finally, we demonstrate the need for several open questions to be answered—chiefly, under what conditions might MFG‐E8‐mediated synapse elimination occur in favor of other mechanisms, and when might its activity be dysregulated, increasing unwanted synapse elimination and neurotoxicity? image
January 2025
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47 Reads
Highly abundant in neurons, the cellular prion protein (PrPC) is an obligatory precursor to the disease‐associated misfolded isoform denoted PrPSc that accumulates in the rare neurodegenerative disorders referred to either as transmissible spongiform encephalopathies (TSEs) or as prion diseases. The ability of PrPC to serve as a substrate for this template‐mediated conversion process depends on several criteria but importantly includes the presence or absence of certain endoproteolytic events performed at the cell surface or in acidic endolysosomal compartments. The major endoproteolytic events affecting PrPC are referred to as α‐ and β‐cleavages, and in this review we outline the sites within PrPC at which the cleavages occur, the mechanisms potentially responsible and their relevance to pathology. Although the association of α‐cleavage with neuroprotection is well‐supported, we identify open questions regarding the importance of β‐cleavage in TSEs and suggest experimental approaches that could provide clarification. We also combine findings from in vitro cleavage assays and mass spectrometry‐based studies of prion protein fragments in the brain to present an updated view in which α‐ and β‐cleavages may represent two distinct clusters of proteolytic events that occur at multiple neighbouring sites rather than at single positions. Furthermore, we highlight the candidate proteolytic mechanisms best supported by the literature; currently, despite several proteases identified as capable of processing PrPC in vitro, in cell‐based models and in some cases, in vivo, none have been shown conclusively to cleave PrPC in the brain. Addressing this knowledge gap will be crucial for developing therapeutic interventions to drive PrPC endoproteolysis in a neuroprotective direction. Finally, we end this review by briefly addressing other cleavage events, specifically ectodomain shedding, γ‐cleavage, the generation of atypical pathological fragments in the familial prion disorder Gerstmann–Sträussler–Scheinker syndrome and the possibility of an additional form of endoproteolysis close to the PrPC N‐terminus. image
January 2025
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4 Reads
The guidance cue netrin‐1 promotes both growth cone attraction and growth cone repulsion. How netrin‐1 elicits diverse axonal responses, beyond engaging the netrin receptor DCC and UNC5 family members, remains elusive. Here, we demonstrate that murine netrin‐1 induces biphasic axonal responses in cortical neurons: Attraction at lower concentrations and repulsion at higher concentrations using both a microfluidic‐based netrin‐1 gradient and bath application of netrin‐1. We find that repulsive turning in a netrin gradient is blocked by knockdown of UNC5C, whereas attractive turning is impaired by knockdown of DCC. TRIM9 is a brain‐enriched E3 ubiquitin ligase previously shown to bind and cluster the attractive receptor DCC at the plasma membrane and regulate netrin‐dependent attractive responses. However, whether TRIM9 also regulated repulsive responses to netrin‐1 remained to be seen. In this study, we show that TRIM9 localizes and interacts with both the attractive netrin receptor DCC and the repulsive netrin receptor, UNC5C. We find that deletion of murine Trim9 alters both attractive and repulsive axon turning and changes in growth cones size in response to murine netrin‐1. TRIM9 was required for netrin‐1‐dependent changes in the surface levels of DCC and UNC5C in the growth cone during morphogenesis. We demonstrate that DCC at the membrane regulates the growth cone area and show that TRIM9 negatively regulates FAK activity in the absence of both repulsive and attractive concentrations of netrin‐1. Together, our work demonstrates that TRIM9 interacts with and regulates both DCC and UNC5C during attractive and repulsive axonal responses to netrin‐1. image
January 2025
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8 Reads
GABAB receptor (GABABR) activation is known to alleviate pain by reducing neuronal excitability, primarily through inhibition of high voltage‐activated (HVA) calcium (CaV2.2) channels and potentiating G protein–coupled inwardly rectifying potassium (GIRK) channels. Although the analgesic properties of small molecules and peptides have been primarily tested on isolated murine dorsal root ganglion (DRG) neurons, emerging strategies to develop, study, and characterise human pluripotent stem cell (hPSC)‐derived sensory neurons present a promising alternative. In this study, hPSCs were efficiently differentiated into peripheral DRG‐induced sensory neurons (iSNs) using a combined chemical and transcription factor‐driven approach via a neural crest cell intermediate. Molecular characterisation and transcriptomic analysis confirmed the expression of key DRG markers such as BRN3A, ISLET1, and PRPH, in addition to GABABR and ion channels including CaV2.2 and GIRK1 in iSNs. Functional characterisation of GABABR was conducted using whole‐cell patch clamp electrophysiology, assessing neuronal excitability under current‐clamp conditions in the absence and presence of GABABR agonists baclofen and α‐conotoxin Vc1.1. Both baclofen (100 μM) and Vc1.1 (1 μM) significantly reduced membrane excitability by hyperpolarising the resting membrane potential and increasing the rheobase for action potential firing. In voltage‐clamp mode, baclofen and Vc1.1 inhibited HVA Ca²⁺ channel currents, which were attenuated by the selective GABABR antagonist CGP 55845. However, modulation of GIRK channels by GABABRs was not observed in the presence of baclofen or Vc1.1, suggesting that functional GIRK1/2 channels were not coupled to GABABRs in hPSC‐derived iSNs. This study is the first to report GABABR modulation of membrane excitability in iSNs by baclofen and Vc1.1, highlighting their potential as a future model for studying analgesic compounds. image
January 2025
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4 Reads
Activation of the brain‐penetrant beta3‐adrenergic receptor (Adrb3) is implicated in the treatment of depressive disorders. Enhancing GABAergic inputs from interneurons onto pyramidal cells of prefrontal cortex (PFC) represents a strategy for antidepressant therapies. Here, we probed the effects of the activation of Adrb3 on GABAergic transmission onto pyramidal neurons in the PFC using in vitro electrophysiology. We found that Adrb3 agonist SR58611A increased both the frequency and the amplitude of miniature IPSCs (mIPSCs). Ca²⁺ influx through T‐type voltage‐gated Ca²⁺ channel (T‐type VGCC) contributed to SR58611A‐enhanced mIPSC frequency. We also found that SR58611A facilitated GABA release probability and the number of releasable vesicles through interaction with T‐type VGCC. SR58611A depolarized somatostatin (Sst) interneurons with no effects on the firing rate of action potential of Sst interneurons. SR58611A‐induced depolarization of Sst interneurons and enhancement of mIPSC frequency required inward rectifier K⁺ channel (Kir). Our results suggest that Kir and T‐type VGCC in Sst interneurons participate in SR58611A‐induced increase in GABA release in PFC. image
January 2025
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19 Reads
Parkinson's disease (PD) is a prevalent neurodegenerative disease caused by the death of dopaminergic neurons within the substantia nigra pars compacta (SNpc) region of the midbrain. Recent genomic and single cell sequencing data identified oligodendrocytes and oligodendrocyte precursor cells (OPCs) to confer genetic risk in PD, but their biological role is unknown. Although SNpc dopaminergic neurons are scarcely or thinly myelinated, there is a gap in the knowledge concerning the physiological interactions between dopaminergic neurons and oligodendroglia. We sought to investigate the distribution of OPCs with regard to the myelination state in the mouse substantia nigra (SN) by high‐resolution imaging to provide a morphological assessment of OPC‐dopaminergic neuron interactions and quantification of cell numbers across different age groups. OPCs are evenly distributed in the midbrain throughout the lifespan and they physically interact with both the soma and axons of dopaminergic neurons. The presence of OPCs and their interaction with dopaminergic neurons does not correlate with the distribution of myelin. Myelination is sparse in the SNpc, including dopaminergic fibers originating from the SNpc and projecting through the substantia nigra pars reticulata (SNpr). We report that OPCs and dopaminergic neurons exist in a 1:1 ratio in the SNpc, with OPCs accounting for 15%–16% of all cells in the region across all age groups. This description of OPC‐dopaminergic neuron interaction in the midbrain provides a first look at their longitudinal distribution in mice, suggesting additional functions of OPCs beyond their differentiation into myelinating oligodendrocytes. image
January 2025
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35 Reads
Synaptic vesicle protein 2A (SV2A) is an abundant synaptic vesicle cargo with an as yet unconfirmed role in presynaptic function. It is also heavily implicated in epilepsy, firstly being the target of the leading anti‐seizure medication levetiracetam and secondly with loss of function mutations culminating in human disease. A range of potential presynaptic functions have been proposed for SV2A; however its interaction with the calcium sensor for synchronous neurotransmitter release, synaptotagmin‐1 (Syt1), has received particular attention over the past decade. In this review we will assess the evidence that the primary role of SV2A is to control the expression and localisation of Syt1 at the presynapse. This will integrate biochemical, cell biological and physiological studies where the interaction, trafficking and functional output of Syt1 is altered by SV2A. The potential for SV2A‐dependent epilepsy to be a result of dysfunctional Syt1 expression and localisation is also discussed. Finally, a series of key open questions will be posed that require resolution before a definitive role for SV2A in Syt1 function in health and disease can be confirmed. image
January 2025
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31 Reads
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Oligodendrocytes, the myelinating cells in the central nervous system, are implicated in several neurological disorders marked by dysfunctional RNA–binding proteins (RBPs). The present study aimed at investigating the role of hnRNP A1 in the proteome of the corpus callosum, prefrontal cortex, and hippocampus of a murine cuprizone–induced demyelination model. Right after the cuprizone insult, we administered an hnRNP A1 splicing activity inhibitor and analyzed its impact on brain remyelination by nanoESI‐LC‐MS/MS label‐free proteomic analysis to assess the biological processes affected in these brain regions. Significant alterations in essential myelination proteins highlighted the involvement of hnRNP A1 in maintaining myelin integrity. Pathways related to sphingolipid and endocannabinoid signaling were affected, as well as the synaptic vesicle cycle and GABAergic synapses. Although behavioral impairments were not observed, molecular changes suggest potential links to memory, synaptic function, and neurotransmission processes. These findings enhance our understanding of the multifaceted roles of hnRNP A1 in the central nervous system, providing valuable insights for future investigations and therapeutic interventions in neurodegenerative and demyelinating diseases. image
January 2025
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22 Reads
Aging is the most common risk factor for Multiple Sclerosis (MS) disease progression. Cellular senescence, the irreversible state of cell cycle arrest, is the main driver of aging and has been found to accumulate prematurely in neurodegenerative diseases, including Alzheimer's and Parkinson's disease. Cellular senescence in the central nervous system of MS patients has recently gained attention, with several studies providing evidence that demyelination induces cellular senescence, with common hallmarks of p16INK4A and p21 expression, oxidative stress, and senescence‐associated secreted factors. Here we discuss the current evidence of cellular senescence in animal models of MS and different glial populations in the central nervous system, highlighting the major gaps in the field that still remain. As premature senescence in MS may exacerbate demyelination and inflammation, resulting in inhibition of myelin repair, it is critical to increase understanding of cellular senescence in vivo, the functional effects of senescence on glial cells, and the impact of removing senescent cells on remyelination and MS. This emerging field holds promise for opening new avenues of treatment for MS patients. image
January 2025
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14 Reads
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Obesity leads to a number of health problems, including learning and memory deficits that can be passed on to the offspring via a developmental programming process. However, the mechanisms involved in the deleterious effects of obesity on cognition remain largely unknown. This study aimed to assess the impact of obesity on the production of sphingolipids (ceramides and sphingomyelins) in the brain and its relationship with the learning deficits displayed by obese individuals. We also sought to determine whether the effects of obesity on brain sphingolipid synthesis could be passed on to the offspring. Learning abilities and brain concentration of sphingolipids in male and female control and obese founder rats (F0) and their offspring (F1) were evaluated, respectively, by the novel object recognition test and by ultra‐performance liquid chromatography tandem mass spectrometry. In addition, a global lipidome profiling of the cerebral cortex and hippocampus was performed. Both male and female F0 rats showed impaired learning and increased concentrations of ceramides and sphingomyelins in the hippocampus and frontal cortex compared to their control counterparts. However, the overall lipidome profile of these brain regions did not change with obesity. Remarkably, the alterations in brain sphingolipid synthesis, as well as the cognitive impairment induced by obesity, were also present in adult F1 male rats born to obese mothers or sired by obese fathers and were associated with enhanced expression of mRNAs coding for enzymes involved in the de novo synthesis of ceramides. These results show that the cognitive deficits and impaired sphingolipid metabolism induced by obesity can be transmitted to the offspring through both the maternal and paternal lineages and suggest that an increase in the brain concentration of sphingolipids could play a causal role in the cognitive deficits associated with obesity. image
January 2025
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31 Reads
The natural compound orotic acid and its anionic form, orotate, play a pivotal role in various biological processes, serving as essential intermediates in pyrimidine de novo synthesis, with demonstrated connections to dietary, supplement, and neurodrug applications. A novel perspective on biomolecular aggregation at the nanoscale, particularly pertinent to neurodegeneration, challenges the established paradigm positing that peptide (amyloid beta) and protein (tau) aggregation mainly govern the molecular events underlying prevalent neuropathologies. Emerging biological evidence indicates a notable role for G‐quadruplex (G4) DNA aggregation in neurodegenerative processes affecting neuronal cells, particularly in the presence of extended (G4C2)n repeats in nuclear DNA sequences. Our study concerns d[(GGGGCC)3GGGG], a G4‐forming DNA model featuring G4C2 repeats that is in correlation with neurodegeneration. Through different investigations utilizing spectroscopic techniques (CD, UV, and thermal denaturations), PAGE electrophoresis, and molecular docking, the study explores the influence of orotate on the aggregation of this neurodegeneration‐associated DNA. A computational approach was employed to construct an in silico model of the DNA aggregate, which involved the docking of multiple G4 units and subsequent integration of the ligand into both the DNA monomer and its in silico aggregated model. The convergence of computational analyses and empirical data collectively supports the hypothesis that orotate possesses the capability to modulate the aggregation of neurodegeneration‐related DNA. Notably, the findings suggest the potential utility of orotate as a neurodrug, especially for the therapy of amyotrophic lateral sclerosis (ALS) and Frontotemporal Dementia (FTD), with its current status as a dietary supplement indicating minimal safety concerns. Additionally, orotate demonstrated a slight increase in mitochondrial dehydrogenase activity as assessed by the MTT assay, which is beneficial for a neurodrug as it suggests a potential role in enhancing mitochondrial function and supporting neuronal health. image
January 2025
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22 Reads
Proton magnetic resonance spectroscopy (MRS) offers a non‐invasive, repeatable, and reproducible method for in vivo metabolite profiling of the brain and other tissues. However, metabolite fingerprinting by MRS requires high signal‐to‐noise ratios for accurate metabolite quantification, which has traditionally been limited to large volumes of interest, compromising spatial fidelity. In this study, we introduce a new optimized pipeline that combines LASER MRS acquisition at 11.7 T with a cryogenic coil and advanced offline pre‐ and post‐processing. This approach achieves a signal‐to‐noise ratio sufficient to reliably quantify 19 distinct metabolites in a volume as small as 0.7 μL within the mouse brain. The resulting high spatial resolution and spectral quality enable the identification of distinct metabolite fingerprints in small, specific regions, as demonstrated by characteristic differences in N‐acetylaspartate, glutamate, taurine, and myo‐inositol between the motor and somatosensory cortices. We demonstrated a decline in taurine and glutamate in the primary motor cortex between 5 and 11 months of age, against the stability of other metabolites. Further exploitation to cortical layer‐specific metabolite fingerprinting of layer I–III to layer VI–V in the primary motor cortex, with the latter showing reduced taurine and phosphoethanolamine levels, demonstrates the potential of this pipeline for detailed in vivo metabolite fingerprinting of cortical areas and subareas. image
January 2025
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25 Reads
Epitranscriptomic regulation of cell functions involves multiple post‐transcriptional chemical modifications of coding and non‐coding RNA that are increasingly recognized in studying human brain disorders. Although rodent models are presently widely used in neuroepitranscriptomic research, the zebrafish (Danio rerio) has emerged as a useful and promising alternative model species. Mounting evidence supports the importance of RNA modifications in zebrafish CNS function, providing additional insights into epitranscriptomic mechanisms underlying a wide range of brain disorders. Here, we discuss recent data on the role of RNA modifications in CNS regulation, with a particular focus on zebrafish models, as well as evaluate current problems, challenges, and future directions of research in this field of molecular neurochemistry. image
January 2025
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37 Reads
Alzheimer's disease (AD) is characterized by the accumulation of amyloid‐beta (Aβ) plaques in the brain, contributing to neurodegeneration. This study investigates lipid alterations within these plaques using a novel, label‐free, multimodal approach. Combining infrared (IR) imaging, machine learning, laser microdissection (LMD), and flow injection analysis mass spectrometry (FIA‐MS), we provide the first comprehensive lipidomic analysis of chemically unaltered Aβ plaques in post‐mortem human AD brain tissue. IR imaging revealed decreased lipid unsaturation within plaques, evidenced by a reduction in the alkene (=C‐H) stretching vibration band. The high spatial resolution of IR imaging, coupled with machine learning‐based plaque detection, enabled precise and label‐free extraction of plaques via LMD. Subsequent FIA‐MS analysis confirmed a significant increase in short‐chain saturated lipids and a concomitant decrease in long‐chain unsaturated lipids within plaques compared to the surrounding tissue. These findings highlight a substantial depletion of unsaturated fatty acids (UFAs) in Aβ plaques, suggesting a pivotal role for lipid dysregulation and oxidative stress in AD pathology. This study advances our understanding of the molecular landscape of Aβ plaques and underscores the potential of lipid‐based therapeutic strategies in AD. image
January 2025
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15 Reads
Enhancing protein O‐GlcNAcylation by pharmacological inhibition of the enzyme O‐GlcNAcase (OGA) has been considered as a strategy to decrease tau and amyloid‐beta phosphorylation, aggregation, and pathology in Alzheimer's disease (AD). There is still more to be learned about the impact of enhancing global protein O‐GlcNAcylation, which is important for understanding the potential of using OGA inhibition to treat neurodegenerative diseases. In this study, we investigated the acute effect of pharmacologically increasing O‐GlcNAc levels, using the OGA inhibitor Thiamet G (TG), in normal mouse brains. We hypothesized that the transcriptome signature in response to a 3 h TG treatment (50 mg/kg) provides a comprehensive view of the effect of OGA inhibition. We then performed mRNA sequencing of the brain using NovaSeq PE 150 (n = 5 each group). We identified 1234 significant differentially expressed genes with TG versus saline treatment. Functional enrichment analysis of the upregulated genes identified several upregulated pathways, including genes normally down in AD. Among the downregulated pathways were the cell adhesion pathway as well as genes normally up in AD and aging. When comparing acute to chronic TG treatment, protein autophosphorylation and kinase activity pathways were upregulated, whereas cell adhesion and astrocyte markers were downregulated in both datasets. AMPK subunit Prkab2 was one gene in the kinase activity pathway, and the increase after acute and chronic treatment was confirmed using qPCR. Interestingly, mitochondrial genes and genes normally down in AD were up in acute treatment and down in chronic treatment. Data from this analysis will enable the evaluation of the mechanisms underlying the impact of OGA inhibition in the treatment of AD. In particular, OGA inhibitors appear to have downstream effects related to bioenergetics which may limit their therapeutic benefits. image
January 2025
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16 Reads
Autism spectrum disorder (ASD) is a complex developmental disorder characterized by several behavioral impairments, especially in socialization, communication, and the occurrence of stereotyped behaviors. In rats, prenatal exposure to valproic acid (VPA) induces autistic‐like behaviors. Previous studies by our group have suggested that the autistic‐like phenotype is possibly related to dopaminergic system modulation because tyrosine hydroxylase (TH) expression was affected. The objective of the present study was to understand the dopaminergic role in autism. Wistar rats on gestational day 12.5 received VPA (400 mg/kg) and behaviors related to rat models of ASD were evaluated in juvenile offspring. Neurochemical and genetic dopaminergic components were studied in different brain areas of both juvenile and adult rats. Prenatal VPA‐induced autistic‐like behaviors in comparison to a control group: decreased maternal solicitations by ultrasonic vocalizations, cognitive inflexibility and stereotyped behavior in the T‐maze test, decreased social interaction and play behavior, as well as motor hyperactivity. Prenatal VPA also decreased dopamine synthesis and activity in the striatum and prefrontal cortex, as well as dopamine transporter, D1 and D2 receptors, and TH expressions. Moreover, prenatal VPA increased TH+ immunoreactive neurons of the ventral tegmental area–substantia nigra complex. In conclusion, the dopaminergic hypoactivity associated with the behavioral impairments exhibited by the rats that received prenatal VPA suggests the important role of this system in the establishment of the characteristic symptoms of ASD in juvenile and adult males. Dopamine was demonstrated to be an important biomarker and a potential pharmacological target for ASD. image
January 2025
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30 Reads
Mutations in the Transcription Factor 20 (TCF20) have been identified in patients with autism spectrum disorders (ASDs), intellectual disabilities (IDs), and other neurological issues. Recently, a new syndrome called TCF20‐associated neurodevelopmental disorders (TAND) has been described, with specific clinical features. While TCF20's role in the neurogenesis of mouse embryos has been reported, little is known about its molecular function in neurons. In this study, we demonstrate that TCF20 is expressed in all analyzed brain regions in mice, and its expression increases during brain development but decreases in muscle tissue. Our findings suggest that TCF20 plays a central role in dendritic arborization and dendritic spine formation processes. RNA sequencing analysis revealed a downregulation of pre‐ and postsynaptic pathways in TCF20 knockdown neurons. We also found decreased levels of GABRA1, BDNF, PSD‐95, and c‐Fos in total homogenates and in synaptosomal preparations of knockdown TCF20 rat cortical cultures. Furthermore, synaptosomal preparations of knockdown TCF20 rat cortical cultures showed significant downregulation of GluN2B and GABRA5, while GluA2 was significantly upregulated. Overall, our data suggest that TCF20 plays an essential role in neuronal development and function by modulating the expression of proteins involved in dendrite and synapse formation and function. image
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The Florey Institute of Neuroscience and Mental Health, Australia