Acta Neuropathologica Communications最新文献

{"title":"ZFTA::YAP1-rearranged ependymoma: is still ZFTA or already YAP?","authors":"Margarita Zaytseva, Agnesa Panferova, Alexandra Tarakanova, Alexey Kislyakov, Natalia Usman, Nikolai Grachev, Ludmila Papusha, Galina Novichkova, Alexander Druy","doi":"10.1186/s40478-026-02352-5","DOIUrl":"10.1186/s40478-026-02352-5","url":null,"abstract":"<p><p>Under the auspices of the World Health Organization Classification of CNS Tumors (5th Edition), supratentorial ependymomas are divided into 2 main molecular groups, comprising tumors that are either ZFTA- or YAP1-fused with the majority harboring ZFTA::RELA fusion. ZFTA-rearranged ependymomas with non-canonical 3´ fusion partners have significant clinical, radiological, and histopathological variability. We report a 5-year-old girl with a left frontal lobe tumor harboring a ZFTA::YAP1 fusion. The patient presented with recurrent absence episodes aggravating to epileptic seizures. The histological appearance of the tumor was inconclusive and shared morphological features of ependymal and glioneuronal neoplasms. Despite the nominal presence of a ZFTA alteration typically associated with aggressive ependymal tumors, the lesion demonstrated prolonged indolent biological behavior. Gene expression assay revealed paradoxical activation of YAP/TAZ signaling and signature unambiguously correspondent to YAP1-activated ependymoma. To our knowledge, this is the first case report demonstrating the molecular background of ZFTA::YAP1-rearranged ependymoma. The case denies the binary classification of supratentorial ependymomas into ZFTA and YAP1 subtypes based entirely on the identity of 5' partner gene involved in the rearrangement. The findings elaborate the concept of molecular pathogenesis for YAP1-rearranged tumors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13540944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148300654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accumulation of membrane repair-associated proteins and mature myostatin are novel markers of muscle pathophysiology in Pompe disease.","authors":"Candice Babarit, Sabrina Jagot, Cindy Schleder, Johan Deniaud, Tiffany Bourgeton, Lydie Lagalice, Lucie Vezzana, Isabelle Leroux, Aurélie Lardenois, Bertrand Evrard, Laurence Dubreil, Jérôme Amiaud, Franck Verrecchia, Chantal Thorin, Alicia Mayeuf-Louchart, Karl Rouger, Marie-Anne Colle","doi":"10.1186/s40478-026-02348-1","DOIUrl":"10.1186/s40478-026-02348-1","url":null,"abstract":"<p><p>Pompe disease is an autosomal recessive metabolic disorder caused by acid alpha-glucosidase deficiency, characterized by progressive skeletal muscle weakness and respiratory insufficiency. Affected muscles exhibit glycogen-filled lysosomes, autophagic build-up, and mitochondrial abnormalities. Despite global myofibrillar disorganization, satellite cells (SCs) fail to activate, due to mechanisms that remain unclear. This study aimed to further characterize the muscle phenotype in Pompe disease, with particular attention to proteins associated with membrane repair processes, as membrane damage is a primary trigger for SC activation. Longitudinal transcriptomic analysis of skeletal muscle from a Pompe disease mouse model, combined with immunohistochemical and biochemical approaches, showed early and sustained overexpression of dysferlin (DYSF), annexin A2 (ANXA2), and AHNAK2. These membrane repair-associated proteins displayed abnormal localization during disease progression, with sarcoplasmic accumulation associated with T-tubules, lysosomes and autophagosomes, respectively. Analysis of muscle biopsies from some patients with late-onset Pompe disease (LOPD) identified similar expression patterns in moderately affected cases, whereas these patterns were less evident or absent in the most severe samples, suggesting stage-dependent redistribution associated with advanced myoarchitectural disorganization. Furthermore, in the mouse model, we observed persistent post-transcriptional accumulation of mature myostatin (MSTN), a key negative regulator of muscle growth, alongside a decrease in the phospho-SMAD3/SMAD3 ratio and reduced SMAD7 expression, which point toward a more complex modulation of its canonical bioactivity rather than a simple increase. Altogether, these findings identify modified distribution proteins linked to membrane repair and dysregulation of MSTN as features of muscle remodeling in Pompe disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548533/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Localized amyloid-β oligomers in the lateral entorhinal cortex drives olfactory dysfunction through aberrant neuronal and network activity.","authors":"Ting Pan, Jiaxing Fang, Xiao Wang, Yimeng Chen, Shan Li, Gaoxue Qiu, Changcheng Sun, Chao Liu, Anan Li, Fengjiao Chen","doi":"10.1186/s40478-026-02354-3","DOIUrl":"10.1186/s40478-026-02354-3","url":null,"abstract":"<p><p>Olfactory dysfunction is one of the most common early features of Alzheimer's disease (AD), yet its underlying neural mechanisms remains unclear. The lateral entorhinal cortex (LEC), a central node in the olfactory network, is among the earliest regions affected by AD pathology. However, the direct evidence supporting a causal link between LEC dysfunction and olfactory disorders in early AD is limited. In the present study, we explored whether and how LEC dysfunction contributes to early AD olfactory dysfunction by injecting amyloid-β_1-42 (Aβ_1-42) oligomers into the LEC to induce localized Aβ oligomers accumulation in this region. Our data demonstrate that localized Aβ oligomers in the LEC impaired odor detection and discrimination in mice. In vivo recordings revealed that Aβ oligomers increased baseline firing and odor-evoked activity in LEC neurons, while also enhancing odor-evoked beta oscillations. This hyperactive state corresponded with disrupted population-level odor decoding. Furthermore, deficits in synaptic structure and impaired synaptic transmission likely underlie the observed behavioral dysfunctions. Overall, these findings indicate that LEC dysfunction is linked to olfactory deficits in early AD, providing direct evidence for the involvement of this region in AD-related olfactory impairment.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548545/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148306550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A stage-resolved neuron-glia transcriptional atlas reveals a glial inflammatory pivot in epilepsy.","authors":"Toni Christoph Berger, Magnus Dehli Vigeland, Hanne Sagsveen Hjorthaug, Cecilie Gjessing Nome, Christoph Patrick Beier, Erik Taubøll, Kaja Kristine Selmer, Kjell Heuser","doi":"10.1186/s40478-026-02323-w","DOIUrl":"10.1186/s40478-026-02323-w","url":null,"abstract":"<p><strong>Background: </strong>Epileptogenesis transforms a healthy brain into an epileptic network, yet the temporal and cell-type-specific molecular events driving this transition remain poorly defined. Neuron-glia interactions are essential in this process, but no study has systematically charted their transcriptional dynamics from the acute insult to chronic epilepsy.</p><p><strong>Methods: </strong>Using the intracortical kainic acid mouse model that recapitulates key hallmarks of mesial temporal lobe epilepsy with hippocampal sclerosis in humans, we performed Fluorescent Activated Nuclear Sorting of NeuN⁺ (neuronal) and NeuN⁻ (glia) nuclei followed by RNA sequencing at 1 h, 24 h, and 3 months after status epilepticus. Differential expression and integrative GO/KEGG analyses resolved stage-specific molecular programs across cell types.</p><p><strong>Results: </strong>The majority of genes differentially expressed in neurons and glia were exclusive to the respective time point investigated. We also identify a sequential reorganization of cellular gene expression changes during epileptogenesis. The acute phase is dominated by a shared stress response and DNA-repair programs in both neurons and glia. At 24 h, glia undergoes a marked transcriptional pivot involving necroptosis-associated, TNFR1/IFN-linked, and COX-2/chemokine pathways, while neurons display immune- and plasticity-related signatures. By 3 months, transcriptional activity is largely confined to glia and enriched for inflammatory, angiogenic, and gliogenic processes, consistent with long-term neurovascular remodeling. Only a few transcripts, including Parp3 (neurons) and Tlr1 (glia), are dysregulated across all stages.</p><p><strong>Conclusion: </strong>These findings reveal an orderly transition from an acute protective-leaning program to a early latent glial inflammatory/regulated-death state, culminating in chronic gliopathy. Our work provides, to our knowledge, the first cell-type-resolved temporal atlas of epileptogenesis and identifies the early latent phase as a mechanistically tractable window for antiepileptogenic intervention.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13576365/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148292978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PCK2 as a potential therapeutic target for aggressive MYC-amplified non-WNT/non-SHH medulloblastoma based on tumor continuum.","authors":"Shuaishuai Xue, Zhengming Zhan, Yonghua Cai, Wei Chen, Ruizhe Chen, Yangqi Mao, Cheng Xie, Jun Liu, Ziyi Luo, Siyuan Liu, Xian Zhang, Peng Li, Hao Long, Ye Song","doi":"10.1186/s40478-026-02304-z","DOIUrl":"10.1186/s40478-026-02304-z","url":null,"abstract":"<p><p>Medulloblastoma, the most common malignant pediatric posterior fossa tumor, exhibits metabolic reprogramming and tumor immune microenvironment heterogeneity in non-WNT/non-SHH subgroups, yet the interplay between these features remains poorly defined. Revealing potential molecular features and hidden therapeutic target, we integrated the transcriptomic data of non-WNT/non-SHH medulloblastoma from GEO and EMBL-EBI databases. Through examination of the Grp3/4 transcriptional continuum, we identified PCK2 (a key gene in the TCA cycle with the highest correlation with continuum score). We validated PCK2 as a driver of proliferation, migration, invasion, glycolysis, and M2 macrophage polarization in MYC-amplified MB cells through short hairpin RNA knockdown experiments. Together, our findings establish metabolic-TIME crosstalk as a prognostic determinant and proffer PCK2 as a therapeutic target for aggressive MB subtypes, offering insights into metabolic subtyping and precision therapy strategies to improve clinical outcomes.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13531781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148293049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clarification of the published survival analysis in H3F3B p.K27I-mutant diffuse midline glioma.","authors":"Ryo Kurokawa, Hirokazu Takami, Yoichi Yasunaga, Osamu Abe","doi":"10.1186/s40478-026-02353-4","DOIUrl":"10.1186/s40478-026-02353-4","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13625366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148282855","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intrathecal (G₄C₂)₁₄₉ delivery in C9orf72-deficient mice yields mild motor dysfunction and ALS/FTD pathological hallmarks.","authors":"Katelyn A Russell, Amelia A Shahrabi, Suleyman C Akerman, Matthew D Byrne, Jeffrey D Rothstein, Davide Trotti, Brigid K Jensen, Aaron R Haeusler","doi":"10.1186/s40478-026-02341-8","DOIUrl":"10.1186/s40478-026-02341-8","url":null,"abstract":"<p><p>A repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), yet existing mouse models incompletely engage spinal regions implicated in disease. Here, an adeno-associated virus encoding (G₄C₂)₁₄₉ repeats was delivered via neonatal intrathecal injection, achieving widespread CNS expression with robust spinal cord targeting. This approach was applied to mice with graded loss of endogenous C9orf72 to interrogate both gain- and loss-of-function mechanisms. Longitudinal motor, behavioral, and pathological analyses revealed that repeat expression primarily drives mild, progressive muscle weakness, whereas coordination deficits were largely genotype dependent. Subtle gait abnormalities and hyperactivity were also observed. Within spinal motor regions, repeat-expressing mice exhibited dipeptide repeat protein accumulation, reduced NeuN-positive area, fewer motor neurons, glial activation, sparse phosphorylated TDP-43 pathology, and increased cryptic TDP-43 splicing. Cross-domain correlations further linked repeat expression, spinal pathology, and motor dysfunction. Collectively, these findings establish that CNS-wide repeat expression combined with reduced C9orf72 produces a coherent, mild ALS/FTD model.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13476920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Patient-derived glioblastoma cultures preserve respiration phenotypes during ex vivo maintenance and show sex-associated differences in migration.","authors":"Veronika Matschke, Philip Glover, Robert Lucaciu, David Pickmann, Martin Scholz, Carsten Theiss, Daniel Hoffmann, Johann Matschke","doi":"10.1186/s40478-026-02349-0","DOIUrl":"10.1186/s40478-026-02349-0","url":null,"abstract":"<p><p>Glioblastoma (GBM) is a highly heterogeneous, invasive brain tumor with profound metabolic plasticity. Patient-derived cultures provide valuable preclinical models, yet the stability and clinical relevance of their metabolic phenotypes during ex vivo maintenance remain unclear. Here, we performed longitudinal functional profiling of mitochondrial respiration, substrate utilization, and migration in primary patient-derived GBM cultures at one and five weeks ex vivo using Seahorse Bioanalyzer assays and wound-healing assays, complemented by exploratory integration with routine clinical parameters (MGMT promoter methylation, p53 expression, sex, and age). Early profiling identified two mitochondrial subgroups distinguished by spare and maximal respiratory capacity, with MGMT promoter methylation observed exclusively in the high-respiration cluster. Over time, most cultures retained their initial phenotype, whereas a subset transitioned from low to high respiration, indicating dynamic adaptation under standardized conditions. Extended culture was accompanied by patient-specific shifts in fuel utilization, including increased glutamine dependency and reduced inter-sample variability in glucose and fatty-acid parameters. Exploratory analyses suggested an association between higher age and lower fatty-acid oxidation capacity and indicated constrained fatty-acid dependency in p53-positive cultures. Migration assays revealed marked inter-sample heterogeneity and a 2-6 times faster gap closure in male-derived than female-derived cultures. Notably, early migratory behavior showed no strong association with OCR-defined metabolic state, and early fuel-flex parameters did not recapitulate OCR cluster structure. Together, these data provide a standardized longitudinal functional benchmark showing that patient-derived GBM cultures preserve intrinsic metabolic heterogeneity while undergoing time-dependent adaptation, and that migration represents an additional, partially independent functional axis. These findings are hypothesis-generating and support stratified, time-sensitive follow-up studies of metabolic and invasive phenotypes in GBM.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13282857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148275552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Higher disease reactivation risk in women after fingolimod withdrawal.","authors":"Marine Massy, Stefanie Marti, Adriane Kutllovci, Niklas Frahm, Firas Fneish, David Ellenberger, Helly Hammer, Andrew Chan, Alexander Leichtle, Fred Lühder, Imke Metz, Maximilian Pistor, Robert Hoepner","doi":"10.1186/s40478-026-02343-6","DOIUrl":"10.1186/s40478-026-02343-6","url":null,"abstract":"<p><strong>Background: </strong>Disease reactivation following cessation of sphingosine 1-phosphate receptor modulators (S1PRM) occurs in ~ 10% of multiple sclerosis (MS) patients. The biological factors underlying this phenomenon remain incompletely understood, including the potential contribution of sex-specific differences.</p><p><strong>Methods: </strong>We performed a systematic review on published literature and adverse event registries (FAERS, EudraVigilance), as of January 2024, focusing exclusively on fingolimod (FTY) withdrawal in individuals with MS. Disease severity after FTY withdrawal was assessed in the experimental autoimmune encephalomyelitis (EAE) mouse model, using untreated EAE mice as controls. S1P receptor expression was analyzed by immunofluorescence in spinal cord tissue from EAE mice and in brain biopsies from MS patients with disease reactivation after FTY withdrawal and MS controls (no prior FTY or S1PRM treatment).</p><p><strong>Results: </strong>Analysis of eight studies (n = 2579) demonstrated an association between female sex and disease reactivation after FTY cessation (odds ratios: 1.09-7.20), corroborated by pharmacovigilance data (FAERS: OR = 2.00, p < 0.0001; EudraVigilance: OR = 2.42, p < 0.0001). Female EAE mice exhibited greater post-FTY treatment disease severity (2.5-fold increase, p < 0.0001) with increased S1PR1 expression on CD3⁺T cells (p < 0.001). Human brain biopsies showed elevated S1PR1 expression on CD3⁺T cells in active demyelinating lesions during disease reactivation compared to inactive demyelinated lesions (p < 0.0001) and controls (p < 0.05).</p><p><strong>Discussion: </strong>Across clinical, experimental, and neuropathological analyses, female sex was associated with more pronounced disease activity following FTY withdrawal. Increased S1PR1 expression in T cells represents a potential cellular correlate of this sex-associated vulnerability and warrants further mechanistic investigation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148269809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methamphetamine hijacks chaperone-mediated autophagy to degrade GPX4, driving ferroptosis-precipitated cognitive decline and addictive pathogenesis.","authors":"Zizhen Si, Dan Zhu, Jianan Lv, Yang Shen, Xidi Wang, Jiahui Zhou, Zhiting Zou, Wenting Wei, Longhui Li, Xing Xu, Yaping Chen, Wenhua Zhou, Yu Liu","doi":"10.1186/s40478-026-02342-7","DOIUrl":"10.1186/s40478-026-02342-7","url":null,"abstract":"<p><p>Methamphetamine (METH) addiction is associated with progressive cognitive decline and maladaptive behaviors, but the molecular mechanisms bridging proteostatic dysfunction to neural circuit degeneration remain poorly defined. We hypothesized that METH hijacks chaperone-mediated autophagy (CMA), a lysosomal quality-control pathway, to drive neurodegeneration through ferroptosis. Using chronic METH self-administration models, hippocampal neurons, and CMA-targeted approaches, we demonstrated that METH coerces CMA components (HSC70-LAMP2A) to recognize a non-canonical ¹²⁴NVKFD¹²⁸ degron on glutathione peroxidase 4 (GPX4), resulting in its lysosomal degradation. This CMA-dependent GPX4 depletion disrupted glutathione recycling, unleashing lethal lipid peroxidation and hippocampal ferroptosis. Critically, neuronal CMA ablation rescued spatial memory deficits and reduced compulsive drug-seeking behaviors, establishing CMA hyperactivity as a causal driver of addiction-related neuropathology. Our findings extend the oxidative stress-centric model of METH toxicity by revealing CMA as a pathological switch that converts physiological proteostasis into a self-destructive cascade. The CMA-GPX4 axis, mechanistically linking protein quality control failure, iron-dependent cell death, and behavioral dysfunction, represents a druggable target, with CMA inhibitors showing preclinical efficacy in mitigating METH-induced neuropsychiatric deterioration. By redefining addiction-associated neurodegeneration as a disorder of hijacked proteostasis, this work provides a unified framework for targeting shared mechanisms in substance use disorders and neurodegenerative diseases.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":" ","pages":""},"PeriodicalIF":6.5,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148256771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}