Frontiers in Molecular Neuroscience最新文献

Tau, a microtubule-associated protein that modulates the dynamic properties of microtubules, is best known for its involvement in tauopathies. Usually expressed as the low molecular (LMW) variants of 45-60 kDa, tau is also expressed as a high molecular weight isoform of 110 kDa, termed Big tau, in neurons of the peripheral nervous system and in a few types of central neurons. Big tau is defined by the inclusion of exon 4a, which adds about 250 amino acids to the projection domain. Despite low sequence conservation the length of the Big tau insert remains remarkably consistent across vertebrates. Here, we analyzed the charge distribution, hydrophobicity, and aggregation propensity of the human sequences of LMW tau, Big tau and the amino acids encoded by exon 4a. Exon 4a amino acids display a pronounced negative net charge of acidic amino acids, an overall hydrophilic composition and low β-sheet content. This contrasts with LMW tau, which is more hydrophobic with extended aggregation-prone motifs including a relatively high β-sheet content. Inclusion of exon 4a in Big tau shifts the global hydrophobicity to intermediate values and reduces predicted β-sheet content, suggesting decreased aggregation propensity. We propose a model in which inclusion of the additional stretch of amino acids encoded by exon 4a shields the aggregation motifs of LMW tau and limits their exposure, which together with its unique biophysical structure, defines the properties of Big tau, Evolutionary analyses across vertebrates (human, rat, zebra finch, frog) confirms the minimal sequence identity and conserved exon size but shows preservation of negative net charge indicating convergent retention of charge-based properties. Hydrophilicity was also broadly conserved, though less invariant across species. These results are consistent with the presence of Big tau in neurons that are resistant to tauopathies that commonly afflict neurons expressing only LMW tau.

The differentiation of pluripotent stem cells into neurons is an essential area of biomedical research, with significant implications for understanding neural development and treating neurological diseases. This study compares neural cultures derived from a common induced pluripotent stem cell line (KYOU-DXR0109B) generated by two widely adopted methods: DUAL SMAD inhibition and exogenous NGN2 overexpression. The DUAL SMAD inhibition method, which differentiates through the neural stem cell stage, produces heterogeneous cultures containing a mix of neurons, neural precursors, and glial cells. Conversely, NGN2 overexpression generates more homogeneous cultures composed predominantly of mature neurons. Transcriptomic analysis revealed significant differences in neural gene markers expression profiles, with cultures from the DUAL SMAD inhibition method enriched in neural stem cell and glial markers, while NGN2 overexpression cultures showed elevated markers for cholinergic and peripheral sensory neurons. This study underscores the importance of choosing appropriate differentiation protocols based on the desired cell types, as each method yields neural cultures with distinct cellular compositions. Understanding these differences can help optimize protocols for specific research and therapeutic applications.

Neurodegenerative disorders pose an increasing burden in the aging society. These conditions share several molecular pathomechanisms, some of which may offer opportunities for therapeutic intervention. In this review, we explore a representative selection of sporadic and hereditary neurodegenerative diseases-namely Alzheimer's disease, cerebral amyloid angiopathy, and the polyQ disorders spinocerebellar ataxia types 2 and 3, as well as Huntington's disease-which all feature the accumulation of intra- or extracellular protein deposits as a hallmark. We place particular emphasis on dysregulations in proteostasis-underlying the formation of these aggregates-and the less commonly addressed disturbances in lipid metabolism. By highlighting potential mechanistic links across different classes of neurodegenerative diseases, we aim to provide new insights that may guide the identification of shared druggable targets and the development of broad-spectrum therapeutic strategies.

The underlying mechanisms of post-traumatic stress disorder (PTSD) are still not fully understood, creating significant obstacles for developing effective therapeutic strategies. Recently, ferroptosis, an iron-dependent form of regulated cell death, has been shown to play a role in several psychiatric disorders, such as major depressive disorder (MDD), stress-induced anxiety, Alzheimer's disease (AD), and Parkinson's disease (PD). While direct evidence for the role of ferroptosis in PTSD is still limited, an increasing number of studies suggest that the pathological features of PTSD may trigger the ferroptosis cascade. Additionally, the typical hallmarks of ferroptosis, such as iron dysregulation, lipid peroxidation, and failure of antioxidant defense systems, may intersect with the pathogenesis of PTSD. Importantly, some treatments for PTSD, such as antioxidants and free radical scavengers, have been proven to inhibit ferroptosis, which further supports the case for ferroptosis as a potential pathogenic mechanism in PTSD. To thoroughly investigate the mechanistic links between ferroptosis and PTSD, we analyze the relevant literature on ferroptosis and PTSD in this review. Our aim is to elucidate the potential relationships between ferroptosis and PTSD, thereby providing novel insights for future research directions. Furthermore, we call for more experimental and clinical studies to explore this relationship further, with the ultimate goal of developing more effective therapeutic strategies for PTSD.

Eph receptor tyrosine kinases and their membrane-bound ephrin ligands constitute a unique bidirectional signaling system that orchestrates cell adhesion, migration, proliferation, and vascular patterning, processes frequently co-opted in malignancy. We conducted an integrative review of preclinical models and clinical cohorts to delineate Eph/ephrin expression landscapes and evaluate functional outcomes in central nervous system neoplasms. In gliomas, particularly glioblastoma multiforme, overexpression of EphA2 and EphA3 correlates with higher tumor grade and increased invasiveness. Conversely, ephrin-A1 and ephrin-A5 exhibit tumor-suppressive properties by promoting receptor internalization and degradation, thereby inhibiting glioma cell proliferation and migration. In medulloblastoma, elevated expression of EphB1 and EphA4 is associated with enhanced angiogenesis and migratory capacity, contributing to tumor progression. In meningiomas, aberrant activation of EphA2 and EphB1 promotes proliferation through engagement with mTOR and ERBB3 signaling pathways. Emerging therapeutic strategies, including ligand-targeted cytotoxins, selective kinase inhibitors, chimeric antigen receptor T cells, and ephrin-based immunomodulators, demonstrate potent anti-tumor efficacy in preclinical settings, highlighting the translational potential of targeting the Eph/ephrin axis. The dualistic nature of Eph/ephrin signaling underscores its translational promise as both a biomarker framework and a precision-guided therapeutic target. Combinatorial receptor-ligand modulation strategies may advance the treatment of central nervous system malignancies by exploiting the context-dependent roles of Eph/ephrin interactions.

Alzheimer's disease (AD) is characterized by the pathological aggregation of amyloid-beta (Aβ) and tau proteins, which display self-templating propagation reminiscent of the prion protein (PrP ^Sc ). Despite these similarities, distinct structural heterogeneities and host interaction mechanisms offer unique avenues for disease-modifying therapies. This review comprehensively synthesizes recent advancements addressing: (1) the conformational commonalities and strain-specificities shared between Aβ/tau and PrP ^Sc ; (2) the spatiotemporal dissemination patterns of pathogenic seeds within neural networks; and (3) the development of biomarkers and therapeutic strategies rooted in prion theory. By integrating insights from prion biology with AD pathogenesis, we propose a comprehensive "conformation-propagation-microenvironment" framework for precision intervention, thereby offering a novel paradigm to surmount current therapeutic limitations.

The saccharopine pathway (SacPath) and the pipecolate pathway (PipPath) catabolize lysine to α-aminoadipate. Although the PipPath has been highlighted as the prominent route operating in the brain, recent work has demonstrated that the SacPath plays a major role in lysine catabolism in the brain. The first two enzymatic steps of the SacPath involve the bifunctional enzyme α-aminoadipate semialdehyde synthase (AASS) harboring the lysine-ketoglutarate reductase (LKR) and the saccharopine dehydrogenase (SDH) domains that convert lysine to α-aminoadipate semialdehyde. Thereafter, the semialdehyde is converted to α-aminoadipate by α-aminoadipate semialdehyde dehydrogenase (AASADH). Mutations abolishing the enzymatic activities of LKR, SDH, and AASADH lead to the genetic diseases hyperlysinemia type I and II, and pyridoxine-dependent epilepsy (PDE), respectively. Hyperlysinemia type I accumulates lysine and causes a benign phenotype without clinical significance. Hyperlysinemia type II accumulates saccharopine, which leads to neuronal disorders and intellectual disability. PDE accumulates α-aminoadipate semialdehyde and its cyclic isomer piperideine-6-carboxylate, which binds pyridoxal 5'-phosphate, disturbs synapses, and causes seizures along with developmental disorders. Another genetic disease, glutaric aciduria type I (GA1), localizes just downstream of the SacPath and is caused by mutations abolishing the enzymatic activity of glutaryl-CoA dehydrogenase (GCDH). GA1 accumulates glutarate and 3-hydroxyglutarate, which are neurotoxic molecules that cause irreversible brain damage. Downregulation of LKR has been shown to reduce the metabolic flux through SacPath and alleviate PDE and GA1 symptoms. This review discusses the role of SacPath and its enzymes as potential targets for developing drugs to treat PDE and GA1, as well as other diseases.

The pathophysiology of neurodegenerative diseases is largely driven by ER stress, contributing to cellular dysfunction and inflammation. Chronic ER stress in skeletal muscle is associated with a deterioration in muscle function, particularly in diseases such as ALS, PD, and AD, which are often accompanied by muscle wasting and weakness. ER stress triggers the UPR, a cellular process designed to restore protein homeostasis, but prolonged or unresolved stress can lead to muscle degeneration. Recent studies indicate that exercise may modulate ER stress, thereby improving muscle health through the enhancement of the adaptive UPR, reducing protein misfolding, and promoting cellular repair mechanisms. This review examines the influence of exercise on the modulation of ER stress in muscle cells, with a particular focus on how physical activity influences key pathways contributed to mitochondrial function, protein folding, and quality control. We discuss how exercise-induced adaptations, including the activation of stress-resilience pathways, antioxidant responses, and autophagy, can help mitigate the negative effects of ER stress in muscle cells. Moreover, we examine the potential therapeutic implications of exercise in neurodegenerative diseases, where it may improve muscle function, reduce muscle wasting, and alleviate symptoms associated with ER stress. By integrating findings from neurobiology, muscle physiology, and cellular stress responses, this article highlights the therapeutic potential of exercise as a strategy to modulate ER stress and improve muscle function in neurodegenerative diseases.

ZNF536, a brain-specific transcriptional repressor, has recently emerged as a candidate risk gene for schizophrenia (SZ), yet its functional role in human neurodevelopment remains poorly understood. We used CRISPR/Cas9 genome editing to generate a dual-allelic ZNF536 knockout model in SH-SY5Y cells, combining a 103 kb deletion encompassing SZ-associated intronic regions with a disruption of zinc finger domains in exon 2. We performed transcriptome profiling of mutant cells undergoing all-trans retinoic acid (ATRA)-induced differentiation and analyzed neurite outgrowth phenotypes. Knockout cells exhibited impaired activation of retinoic acid receptor (RAR) target genes, reduced neurite outgrowth, and failure of neuronal maturation. Gene set enrichment analysis uncovered dysregulation of E2F4-mediated cell cycle pathways. The targeted intronic deletion altered the expression of multiple SZ-associated genes, supporting the functional importance of cis-regulatory elements within ZNF536. These findings identify ZNF536 as a critical regulator of RA-responsive gene networks and neuronal differentiation, modulating neurogenic commitment through coordinated control of transcriptional repression and cell proliferation, and offer new mechanistic insights into its contribution to schizophrenia pathogenesis.

Background: The learning and memory impairments observed in Alzheimer's disease (AD) are strongly associated with impaired neurogenesis in the hippocampal region. Our previous research has highlighted the potential of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) in ameliorating AD-related pathological changes. As a key metabolic regulator, PGC-1α is highly expressed in energy-demanding tissues such as the hippocampus. However, its specific roles and underlying mechanisms in AD-associated neurogenesis remains largely unclear.

Objective: This study aimed to elucidate the precise role and molecular mechanisms by which PGC-1α regulates the survival of newly generated neurons during neurogenesis in the AD-affected hippocampus.

Methods: Using combined models of PGC-1α overexpression in the hippocampal dentate gyrus (DG) of AD-model mice and PGC-1α knockout mice, we investigated the effects of gain- and loss-of-function of PGC-1α on the regulation of the FNDC5/BDNF/TrkB signaling pathway, as well as on the survival of newborn neurons in the AD-affected hippocampus.

Results: Our findings demonstrate that PGC-1α enhances the survival of newly generated neurons in the AD-affected hippocampus. Furthermore, PGC-1α functions acts as an upstream regulator of the FNDC5/BDNF/TrkB signaling pathway, and its knockdown suppresses neuronal survival by inhibiting this pathway.

Conclusion: These results indicate that PGC-1α serves as a critical mediator in the FNDC5/BDNF/TrkB signaling pathway within newborn neurons. Enhancing PGC-1α expression, either pharmacologically or through alternative approaches, may therefore represent a promising therapeutic strategy for Alzheimer's disease.