Journal of Neurochemistry最新文献

{"title":"Sex-Dependent Neurochemical Encoding of Acute Social Experience in Adult CD1 Mice","authors":"Garikoitz Azkona,&nbsp;Alina Díez-Solinska,&nbsp;Oihane Saez-Atxukarro,&nbsp;Luna Ochoteco-Perales,&nbsp;Garikoitz Beitia-Oyarzabal,&nbsp;Oscar Vegas","doi":"10.1111/jnc.70509","DOIUrl":"10.1111/jnc.70509","url":null,"abstract":"<p>Acute social interaction rapidly engages physiological and neurochemical systems, yet the extent to which these responses differ between sexes remains incompletely understood. Here, we investigated behavioural, endocrine and region-specific neurochemical responses to a brief social challenge using the social interaction test in adult male and female CD1 mice. Behavioural performance was comparable between sexes, with similar levels of social interaction and locomotor activity. In contrast, endocrine measures revealed a robust stress response, as corticosterone markedly increased after social challenge. Estradiol and progesterone levels also increased following the social challenge, whereas testosterone exhibited the expected sexual dimorphism. Neurochemical profiling revealed widespread and region-dependent effects. The brainstem showed manipulation-driven increases in glutamatergic and catecholaminergic markers across sexes. In the striatum, social interaction preferentially enhanced glutamatergic metabolites in males, whereas females displayed stronger monoaminergic signatures. The hippocampus exhibited the most pronounced sex-dependent modulation, involving amino-acid precursors, catecholaminergic turnover indices, noradrenergic metabolites and kynurenine-pathway ratios. By contrast, neurochemical organisation in the prefrontal cortex was predominantly shaped by baseline sexual dimorphism rather than acute social exposure. Correlation analyses between plasma hormones and regional neurochemical markers revealed limited and inconsistent associations, suggesting a relative dissociation between endocrine and neurochemical responses to the social challenge. Together, these findings demonstrate that acute social interaction induces broad endocrine and neurochemical adaptations while revealing distinct, region-specific sex signatures in neurochemical regulation.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70509","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Brainstem Astrocytes Regulate Estrus-Dependent Oscillations in Food Intake","authors":"K. Selin Ozkaya,&nbsp;Ceyda Yalcin,&nbsp;Emily E. Haar,&nbsp;Ruchi Bhagat,&nbsp;Kirsteen N. Browning","doi":"10.1111/jnc.70498","DOIUrl":"10.1111/jnc.70498","url":null,"abstract":"<p>Previous studies have shown that dorsal vagal complex (DVC) astrocytes play important roles in homeostatic regulation of food intake and caloric balance, specifically upregulation of NMDA receptor-mediated glutamatergic signaling to brainstem dorsal motor nucleus of the vagus (DMV) motoneurons restores caloric balance following exposure to caloric dense diets. DMV neurons are critical to the regulation of gastric functions, including motility, tone, and emptying; hence food intake and energy homeostasis. Prior studies have also shown that caloric intake in female rats fluctuates across the estrus cycle, with food intake being lowest during periods of high estrogen levels. The aim of the current study was to investigate whether these estrus-cycle dependent oscillations in food intake also involve DVC astrocyte adaptation. Immunohistochemical measurement of astrocytes across the estrus cycle uncovered an increase in glial-fibrillary acidic protein immunoreactivity (GFAP-IR) as well as an increase in astrocyte morphological complexity associated with high estrogen levels. Chemogenetic inhibition of DVC astrocytes eliminated food intake oscillations, whereas chemogenetic activation resulted in a consistent decrease in food intake, regardless of estrus status. Electrophysiological recordings from DMV neurons revealed that the estrus-dependent decrease in food intake was associated with activation of DMV NMDA receptors, and pharmacological inhibition of either estrogen receptors or brainstem astrocytes prevented this mechanism. In contrast, application of estradiol uncovered astrocyte- and NMDA-receptor dependent signaling to DMV neurons in low estrogen states. The findings of the present study demonstrate that DVC astrocytes and/or NMDA signaling play a fundamental role in estrogen-dependent fluctuations in food intake and energy homeostasis.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70498","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148276973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “ATG14-Mediated SNARE Complex Activation Promotes ΔFosB Degradation to Ameliorate Levodopa-Induced Dyskinesia”","authors":"","doi":"10.1111/jnc.70494","DOIUrl":"10.1111/jnc.70494","url":null,"abstract":"<p>Wu, Y., K. Liu, Z. Zhang, et al. 2026. “ATG14-Mediated SNARE Complex Activation Promotes ΔFosB Degradation to Ameliorate Levodopa-Induced Dyskinesia.” <i>Journal of Neurochemistry</i> 170, no. 4: e70431. https://doi.org/10.1111/jnc.70431.</p><p>In the funding statement of the published article, the support from the National Natural Science Foundation of China was unintentionally omitted. The correct and complete funding acknowledgment is as follows:</p><p>This work was supported by the National Natural Science Foundation of China (Grant No. 82371270) and the Beijing Medical Award Foundation (Neuroscience Innovation and Development Research Project, Grant No. YXJL-2022-0351-0412).</p><p>We apologize for this error.</p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70494","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ischemia-Induced Post-Translational Modifications of GLT-1 Mediate Aberrant Trafficking and Impaired Glutamate Uptake","authors":"Simran Kaur Gill,&nbsp;Katelyn Louise Reeb,&nbsp;Max Kroll,&nbsp;Ole V. Mortensen,&nbsp;Andréia C. K. Fontana","doi":"10.1111/jnc.70497","DOIUrl":"10.1111/jnc.70497","url":null,"abstract":"<p>Glutamate transporters are essential for maintaining CNS homeostasis by clearing extracellular glutamate following synaptic transmission. Dysregulation of these transporters contributes to glutamate-mediated excitotoxicity across numerous neurological disorders, including ischemic stroke, underscoring their potential as therapeutic targets. However, the regulatory response of these transporters following ischemic insult remains poorly defined. In this study, using a model of oxygen–glucose deprivation in primary rat glial cultures, we report aberrant trafficking of the astrocytic glutamate transporter GLT-1 following ischemic insult. This response is characterized by increased transporter internalization and degradation, accompanied by reduced glutamate uptake capacity. Focusing on post-translational modifications (PTMs), we found that GLT-1 ubiquitination is markedly increased after ischemic insult and coincides with transporter internalization. Importantly, disrupting this ubiquitination interaction through mutation of C-terminal GLT-1 lysine residues restores GLT-1 surface expression and rescues glutamate uptake capacity through preventing early endosome 1 (EEA1)-mediated internalization. Additionally, we report that inhibition of C-terminal GLT-1 PTMs confers neuroprotection following ischemic insult in organotypic hippocampal brain slices. Together, these findings demonstrate that ischemia-induced dysregulation of GLT-1 trafficking plays a critical role in impaired glutamate clearance and cellular recovery, highlighting GLT-1 ubiquitination as a potential therapeutic target for ischemic injury.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.6,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70497","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148258512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Brain Cholesterol Homeostasis in Alzheimer's Disease: Mechanisms and Therapeutic Perspectives","authors":"Myuri Ruthirakuhan,&nbsp;Ameer Y. Taha,&nbsp;Walter Swardfager","doi":"10.1111/jnc.70492","DOIUrl":"10.1111/jnc.70492","url":null,"abstract":"<p>Cholesterol is a fundamental component of the central nervous system, supporting myelin integrity, synaptic structure, membrane organization, and neuronal signaling. Because the brain is largely isolated from peripheral cholesterol pools, tight regulation of brain cholesterol homeostasis is required to sustain neuronal and glial function across the lifespan. Growing evidence indicates that disruption of this balance is not merely a downstream consequence of neurodegeneration, but an upstream contributor to Alzheimer's disease (AD) pathogenesis. Altered brain cholesterol homeostasis has been linked to amyloidogenic processing, tau pathology, neuroinflammation, synaptic dysfunction, and cerebrovascular injury. This review synthesizes current evidence showing how multiple converging stressors, including peripheral hypercholesterolemia, neurodegeneration, oxidative stress, and inflammatory signaling, perturb brain cholesterol regulation. These drivers disrupt the coordinated processes of cholesterol synthesis, metabolism, and transport, shifting the system from tightly regulated sterol flux toward impaired clearance, abnormal lipid distribution, and membrane instability. Such disturbances remodel membrane lipid composition, alter lipid raft organization, and impair glial–neuronal lipid coupling, thereby accelerating amyloid-β production, tau-related vulnerability, innate immune activation, and neurovascular dysfunction. Finally, we provide an overview of therapeutic strategies aimed at restoring cholesterol balance, and highlight the potential of integrated, multi-target strategies to complement amyloid- and tau-directed therapies. By clarifying how disruptions in brain cholesterol homeostasis link systemic and central stressors to AD pathology, this review identifies cholesterol regulation as a critical, upstream axis for therapeutic intervention and disease prevention.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70492","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Septins in the Middle—Makers and Breakers of Membrane Contact Sites","authors":"TrishaJean J. Holt,&nbsp;Elias T. Spiliotis","doi":"10.1111/jnc.70495","DOIUrl":"10.1111/jnc.70495","url":null,"abstract":"<p>Intracellular communication in neurons requires precise coordination of signals across geometrically complex and highly compartmentalized cellular architectures. Membrane contact sites (MCS)—specialized junctions where two organelles are closely apposed without undergoing fusion—have emerged as key organizational hubs enabling efficient exchange of ions, lipids, and metabolites, yet the cytoskeletal proteins that organize and regulate these junctions remain poorly understood. Here, we review evidence that septins—a conserved family of heteromeric GTP-binding proteins that assemble into filamentous oligomers and polymers—function as integral components of MCS in neurons and beyond. Septins associate with hyperboloid, hourglass-shaped membrane curvatures and distinct membrane domains and organelles through polybasic motifs, amphipathic helices, and transmembrane domains. We review how septins establish diffusion barriers at endoplasmic reticulum (ER)-plasma membrane (PM) contacts in budding yeast and consider evidence that analogous mechanisms operate at dendritic branch points and spine necks in mammalian neurons. We examine septin roles in regulating store-operated calcium entry at ER-PM contacts and explore how septins regulate membrane contacts at presynaptic active zones. Additionally, we highlight how septins organize membrane contacts between host organelles and intracellular pathogens, scaffolding autophagic, mitochondrial, and lysosomal membranes for bacterial clearance. Collectively, these findings support the view that septins constitute a versatile and underappreciated class of MCS tethers whose paralog- and isoform-specific complex compositions may confer spatial and functional selectivity for distinct MCS, opening new avenues for understanding organelle connectivity in health and disease.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70495","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148225999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Lysine Deacetylation Inhibition Alone or in Combination With Arimoclomol on TDP-43 Proteinopathy","authors":"Serena Scozzari,&nbsp;Stefano Fabrizio Columbro,&nbsp;Monica Favagrossa,&nbsp;Massimo Tortarolo,&nbsp;Alfredo Cagnotto,&nbsp;Mario Salmona,&nbsp;Giovanni De Marco,&nbsp;Caterina Bendotti,&nbsp;Andrea Calvo,&nbsp;Laura Pasetto,&nbsp;Valentina Bonetto","doi":"10.1111/jnc.70493","DOIUrl":"10.1111/jnc.70493","url":null,"abstract":"<p>Cytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. Peptidyl-prolyl cis-trans isomerase A (PPIA) interacts with TDP-43 and influences its aggregation and function. This interaction is facilitated by PPIA Lys-acetylation. Here, we investigated whether restoring lysine acetylation homeostasis exerts protective effects on TDP-43 proteinopathy in vitro and in vivo and how this relates with PPIA. We found that vorinostat/SAHA, a broad-spectrum histone deacetylase (HDAC) inhibitor that increases PPIA acetylation, is able to reverse TDP-43 mislocalization in a cellular model of TDP-43 proteinopathy. We confirmed its effects in peripheral blood mononuclear cells from ALS patients and explored its impact on TDP-43 proteinopathy and PPIA acetylation in the Thy1-hTDP-43 mouse model. Thy1-hTDP-43 mice treated with SAHA showed a delayed onset of TDP-43 pathology, associated with PPIA nucleus-cytoplasm redistribution, lower neurodegeneration and neuroinflammation, and improved neuromuscular function markers. However, these effects were transient. When combined with arimoclomol, a heat shock protein co-inducer, a mitigation of the neurodegeneration was sustained. A synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing phosphorylated TDP-43 accumulation in the sciatic nerve and acetylcholine receptor γ-subunit expression in gastrocnemius muscle. This study suggests that HDAC inhibition could be beneficial in restoring TDP-43 localization and function through multiple mechanisms, including modulation of PPIA acetylation. The combination of lysine deacetylation inhibition and arimoclomol shows a synergistic effect in vivo and has potential as a therapeutic approach for patients.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70493","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Long Haul: Microtubule Motors as the Essential Supply Line for Neuronal Longevity","authors":"Emma D. Turner,&nbsp;Alison E. Twelvetrees","doi":"10.1111/jnc.70496","DOIUrl":"10.1111/jnc.70496","url":null,"abstract":"<p>The extreme morphology and polarised architecture of neurons require the highly sophisticated microtubule transport system for both construction and lifelong survival. Genomic evidence from an expanding landscape of human mutations supports the essential role of the microtubule transport machinery. During neurodevelopment, mutations disrupt the proliferation and migration of neuronal precursors, as well as the initial establishment of polarity. In the mature nervous system, the reliance on microtubule transport shifts to the long-term maintenance of axon integrity and synaptic proteostasis. Across the motor proteins responsible for long distance transport in neurons, mutations highlight a specific vulnerability of long axons to transport failure in Hereditary Spastic Paraplegia (HSP), Charcot Marie Tooth disease Type 2 (CMT2), Spinal Muscular Atrophy (SMA), Perry Syndrome, and Amyotrophic Lateral Sclerosis (ALS) amongst others. Due to the role of microtubule motors in development and maintenance, there is frequently a phenotypic spectrum within a single gene of the microtubule transport system. For example, mutations in dynein motors are linked both to malformations of cortical development and specific motor neuron loss in SMA-LED (Spinal Muscular Atrophy with Lower Extremity Predominance). By synthesising genetic evidence, this review illustrates how specific molecular failures, ranging from motor-domain kinetics to cargo binding, can inform our understanding of neuronal homeostasis. Ultimately, we argue that microtubule transport is not merely a cellular utility, but a key determinant of neuronal longevity.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70496","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226074","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Neuroinflammation in Depression: The Integrative Role of Sigma-1 Receptor Modulation","authors":"Jing-Ya Wang,&nbsp;De-Yi Yang,&nbsp;Yun-Feng Li,&nbsp;Peng Ren","doi":"10.1111/jnc.70490","DOIUrl":"10.1111/jnc.70490","url":null,"abstract":"<p>Depression is a leading cause of global disability, yet remains insufficiently treated by conventional monoaminergic antidepressants, which are limited by their delayed onset, variable efficacy, and significant side effects. Accumulating evidence positions neuroinflammation, driven by glial dysfunction, peripheral-central immune crosstalk, and associated cellular stress pathways as a pivotal upstream mechanism in the pathogenesis of depression, contributing to both neurotransmitter dysregulation and impaired synaptic plasticity. This review examines the integrative role of the Sigma-1 receptor (Sig-1R), a ligand-operated chaperone predominantly localized at the mitochondria-associated endoplasmic reticulum membrane (MAM), as a promising therapeutic target for mitigating this neuroinflammatory cascade. We systematically synthesize preclinical evidence demonstrating that pharmacological activation of Sig-1R produces broad anti-neuroinflammatory effects, including the promotion of microglial homeostasis and a shift toward an anti-inflammatory phenotype, attenuation of reactive astrogliosis, suppression of key pro-inflammatory signaling hubs such as NF-κB and the NLRP3 inflammasome, and mitigation of oligodendrocyte dysfunction. Beyond immunomodulation, Sig-1R activation alleviates endoplasmic reticulum stress, enhances autophagic and mitophagic clearance, supports mitochondrial bioenergetics, and strengthens endogenous antioxidant defenses. Together, these actions disrupt the vicious cycle linking cellular stress, inflammation, and synaptic impairment. We also evaluate advances in representative Sig-1R agonists and review available clinical trial data, including results on the novel multi-target agent AXS-05. Genetic and pharmacological loss-of-function studies further emphasize the essential role of Sig-1R in mood regulation and stress resilience. In summary, the Sigma-1 receptor serves as a key regulator of cellular homeostasis and adaptation. Its agonists represent a promising therapeutic strategy that moves beyond symptomatic monoaminergic modulation to mechanistically target the core inflammatory and proteostatic disturbances in depression, offering the potential for improved treatment efficacy.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70490","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Biological Framework for Parkinson's Disease: Advances in α-Synuclein–Centered Biomarkers and Staging","authors":"Taku Hatano,&nbsp;Chin-Hsien Lin,&nbsp;Francisco Cardoso","doi":"10.1111/jnc.70491","DOIUrl":"10.1111/jnc.70491","url":null,"abstract":"<p>Parkinson's disease (PD) is a neurodegenerative disorder marked by substantial heterogeneity in pathological distribution, disease trajectories, and coexisting neuropathologies. Despite this biological complexity, current diagnosis and staging of PD remain largely anchored in clinical manifestations. Neuronal aggregation of misfolded α-synuclein and degeneration of the nigrostriatal dopaminergic system precede the onset of motor symptoms; this phase is termed the prodromal stage of PD. Therefore, clinically based frameworks inherently limit early detection and stratification. In contrast, Alzheimer's disease has undergone a paradigm shift toward a biomarker-driven biological definition, prompting a similar reappraisal of PD as a biologically defined disease continuum. Accumulating evidence indicates that pathological α-synuclein aggregates in PD extend beyond the central nervous system and exhibit heterogeneous patterns of initiation and propagation. Methodological advances have expanded the capacity to detect these pathological species in vivo. In particular, α-synuclein seed amplification assays (SAA) enable the detection of seeding-competent α-synuclein species in biofluids and peripheral tissues, providing evidence consistent with α-synuclein pathology; however, SAA should not be interpreted as a direct reflection of disease stage, progression, or pathological burden. Furthermore, the development of α-synuclein positron emission tomography ligands offers the prospect of non-invasive visualization of pathological burden, spatial distribution, and longitudinal target engagement, thereby complementing biofluid-based approaches. Together, these biomarker advances underpin emerging biologically anchored classification and staging frameworks, such as the SynNeurGe system and the Neuronal α-Synuclein Disease Integrated Staging System (NSD-ISS). These frameworks integrate α-synuclein pathology, neurodegeneration, genetic background, and clinical features to define disease identity and progression across asymptomatic, prodromal, and manifest stages. We synthesize recent advances in α-synuclein–centered biomarkers and biological staging frameworks and discuss how their convergence is beginning to reshape PD from a primarily symptom-based diagnosis toward a molecularly grounded disease continuum. This transition has the potential to complement clinically defined PD with biologically informed perspectives.</p><p>\u0000 \u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure>\u0000 </p>","PeriodicalId":16527,"journal":{"name":"Journal of Neurochemistry","volume":"170 6","pages":""},"PeriodicalIF":4.0,"publicationDate":"2026-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/jnc.70491","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148205025","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}