Autophagy最新文献

{"title":"Cardiac fibroblast-derived CCN1 aggravates diabetic cardiomyopathy through ITGAV-ITGB1/integrin αvβ1-mediated autophagy inhibition.","authors":"Bo-Ang Hu, Lei Zhang, Ming Song, Yan-Ru Kong, Ya-Qiong Jiao, Xu Jia, Ping Zhu, Yu-Lin Li, Yun Ti, Wei Zhang, Zhi-Hao Wang, Ming Zhong","doi":"10.1080/15548627.2026.2667721","DOIUrl":"10.1080/15548627.2026.2667721","url":null,"abstract":"<p><p>Cardiac fibrosis is a defining pathological feature of diabetic cardiomyopathy (DCM), and excessive activation of cardiac fibroblasts plays a critical role in regulating cardiomyocyte function through paracrine signaling. CCN1 (cellular communication network factor 1), an extracellular matrix protein involved in intercellular communication, has been suggested to influence cardiac remodeling, although its specific impact on cardiomyocytes in DCM has remained unclear. In this study, we found that CCN1 expression was markedly elevated in cardiac tissues from DCM mouse models and in insulin-resistant cell models, with fibroblasts serving as the primary source. Proteomic analysis and co-culture experiments demonstrated that CCN1 suppressed cardiomyocyte macroautophagy/autophagy. To determine its role in vivo, we generated fibroblast-specific <i>ccn1</i> knockout mice and established a DCM model, demonstrating that <i>ccn1</i> deletion ameliorated cardiac dysfunction and restored autophagic activity. We further identified ITGAV-ITGB1/integrin αvβ1 as the receptor mediating CCN1 signaling in cardiomyocytes. Molecular dynamics simulations and co-immunoprecipitation experiments confirmed that CCN1 engaged ITGAV-ITGB1/integrin αvβ1 through its cysteine-knot-containing (CT) domain. Mechanistically, this interaction activated the downstream PTK2/FAK-MTOR signaling pathway, leading to inhibition of cardiomyocyte autophagy. Together, these findings reveal a previously unrecognized fibroblast-cardiomyocyte signaling axis in which fibroblast-derived CCN1 drives DCM progression by suppressing autophagy through ITGAV-ITGB1/integrin αvβ1-dependent signaling. This work provides mechanistic insight into the pathogenesis of DCM and identifies CCN1 as a potential therapeutic target for mitigating disease onset and progression.<b>Abbreviations</b>: AAV9: adeno-associated virus serotype 9; ADGRE1/EMR1/F4/80: adhesion G protein-coupled receptor E1; BafA1: bafilomycin A<sub>1</sub>; BSA: bovine serum albumin; C8: compound 8; CCN1: cellular communication network factor 1; CF: cardiac fibroblast; CSA: cross-sectional area; DCM: diabetic cardiomyopathy; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; ELISA: enzyme-linked immunosorbent assay; HE: hematoxylin and eosin; HFD: high-fat diet; HG: high glucose; IR: insulin resistance; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MD: molecular dynamics; MTOR: mechanistic target of rapamycin kinase; NRCM: neonatal rat cardiomyocyte; PDGFRA: platelet derived growth factor receptor alpha; PECAM1/CD31: platelet and endothelial cell adhesion molecule 1; PTK2/FAK: protein tyrosine kinase 2; PTPRC/CD45: protein tyrosine phosphatase receptor type C; RPS6KB1: ribosomal protein S6 kinase B1; S100A4/FSP1: S100 calcium binding protein A4; SQSTM1/p62: sequestosome 1; STZ: streptozotocin; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling; WGA: wheat germ agglutinin.<","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-24"},"PeriodicalIF":14.3,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147792026","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advancing targeted protein degradation: pLIRTAC's role in glioma and CAR-T cell therapy.","authors":"Kunjian Lei, Yishuang Li, Zhihong Zhou, Jingying Li, Linzhen Huang, Wenji Liu, Kai Huang, Xingen Zhu","doi":"10.1080/15548627.2026.2668653","DOIUrl":"10.1080/15548627.2026.2668653","url":null,"abstract":"<p><p>The rapid development of targeted protein degradation (TPD) has shown profound effects on disease treatment. Precise and effective targeted degradation tools that target endogenous proteins are essential to accelerate advances in treatment methods. Selective macroautophagy/autophagy relies on the activity of related receptors to achieve the degradation of specific intracellular components in lysosomes, but the methodology of selective autophagy for tumor therapy and chimeric antigen receptor (CAR)-T cell modification is yet unexplored. Here, we developed a peptide-based LC3-interacting region-targeting chimera (pLIRTAC) that accurately and efficiently targeted the degradation of AKT1 for glioma treatment. pLIRTAC could also inhibit the development of tumor cells by <i>in vitro</i> delivery after purification. For CAR-T cell therapy, pLIRTAC could significantly improve the efficacy of CAR-T cell-targeted lysis of tumor cells both <i>in vitro</i> and <i>in vivo</i>. pLIRTAC binds to autophagy-associated proteins through LC3-interacting region (LIR) motifs and to target proteins through protein-targeting short peptides, and targets the protein of interest (POI) based on the selective autophagy lysosomal pathway. pLIRTAC has been remarkably successful both <i>in vivo</i> and <i>in vitro</i>, providing a robust and effective tool for the control of endogenous abnormal proteins in cells, and can potentially further expand the therapeutic application of TPD technology.<b>Abbreviation:</b> ATG8s: mammalian Atg8 (autophagy related 8)-family proteins; Baf-A1: bafilomycin A₁; CAR: chimeric antigen receptor; CQ: chloroquine; CRISPR: clustered regularly interspaced short palindromic repeats; EBSS: Earle's balanced salt solution; LIR: LC3-interacting region; 3 MA: 3-methyladenine; MFI: mean fluorescence intensity; pLIRTAC: peptide-based LC3-interacting region-targeting chimera; POI: protein of interest; PROTAC: proteolysis-targeting chimera; SARS: selective autophagy receptors; TPD: targeted protein degradation.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-17"},"PeriodicalIF":14.3,"publicationDate":"2026-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DEHP disrupts lipid metabolism via autophagy hyperactivation and mitochondrial dysfunction.","authors":"Si-Yu Yu, Qiao Liu, Yao-Hua Gu, Wen-Zhuo Han, Ao-Jing Han, Jun Xiong, Tian-Zhou Li, Qiu-Shuang Hu, Fang-Ying Gang, Chen-Qian Zhao, Tian Feng, Jianbo Tian, Xiaoping Miao, Xue-Jie Yu, Neng-Bin Xie, Bi-Feng Yuan","doi":"10.1080/15548627.2026.2668651","DOIUrl":"10.1080/15548627.2026.2668651","url":null,"abstract":"<p><p>Di(2-ethylhexyl) phthalate (DEHP) is a widely used industrial plasticizer, raising global concerns due to its potential endocrine-disrupting effects and environmental persistence. Human exposure to DEHP primarily occurs through the ingestion of contaminated food and water, inhalation of airborne particles, and dermal contact with products containing DEHP. Understanding the toxicological mechanisms of DEHP is essential for evaluating its health risks and developing effective strategies to mitigate its adverse effects. In this study, we conducted long-term exposure experiments to DEHP using both an animal model and in vitro system to investigate the complex interplay among DNA methylation, hyperactivation of macroautophagy/autophagy, mitochondrial dysfunction, and lipid accumulation induced by DEHP. The results revealed that DEHP exposure induced the degradation of DNMT1 (DNA methyltransferase 1) by enhancing its interaction with the autophagy-related protein SQSTM1 (sequestosome 1). DNMT1 degradation resulted in decreased methylation of the promoter regions of genes associated with autophagosome formation, subsequently increasing their expression. The resulting demethylation excessively activated autophagy, contributing to mitochondrial dysfunction and lipid accumulation in the liver. This study uncovered a previously unrecognized interplay among hyperactivation of autophagy, mitochondrial dysfunction, and lipid accumulation in the context of DEHP exposure. These findings enhanced our understanding of DEHP's toxicity and underscored concerns about the long-term health effects of environmental pollutants, particularly regarding metabolic diseases.<b>Abbreviation:</b> ATG5:autophagy related 5; ATG16L1: autophagy related 16 like 1; BECN1:beclin 1; COX4/COXIV: cytochrome c oxidase subunit 4; BS-seq:bisulfite sequencing; DCFH-DA: 2',7'-dichlorodihydrofluoresceindiacetate; DEHP: di(2-ethylhexyl) phthalate; DNMT1: DNAmethyltransferase 1; DNMT3A: DNA methyltransferase 3A; FABP4: fattyacid binding protein 4; FASN: fatty acid synthase; LPL: lipoproteinlipase; MAP1LC3/LC3: microtubule associated protein1 light chain 3; NAFLD: nonalcoholic fatty liver disease; NR1H3:nuclear receptor subfamily 1 group H member 3; PPARG: peroxisomeproliferator activated receptor gamma; RB1CC1: RB1 induciblecoiled-coil 1; SQSTM1: sequestosome 1; SREBF2: sterol regulatoryelement binding transcription factor 2; VDAC1: voltage dependentanion channel 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-16"},"PeriodicalIF":14.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147824629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SETDB1 enhances starvation-induced lipophagy by inhibiting m⁶A-mediated mRNA decay via DDX5 methylation.","authors":"Wenjun Wang, Yanhong Wang, Lige Hou, Xiaoyun Wei, Wenqi Guo, Juan Huang, Junyang Tan, Qiuxia Lu, Qi Zhao, Zhenyu Ju, Jianshuang Li, Qinghua Zhou","doi":"10.1080/15548627.2026.2669984","DOIUrl":"https://doi.org/10.1080/15548627.2026.2669984","url":null,"abstract":"<p><p>Lipophagy, a selective form of macroautophagy/autophagy, degrades lipid droplets (LDs) to provide energy and is implicated in metabolic disorders. The molecular mechanism underlying lipophagy induction remains incompletely understood. This study explored the role of SETDB1 in starvation-induced autophagy and lipophagy. We demonstrate that SETDB1 deficiency exacerbates starvation-induced hepatic lipid accumulation by inhibiting lipophagy. Mechanistically, starvation promotes ATM-mediated phosphorylation of SETDB1, which enhances its interaction with and methylation of the RNA helicase DDX5. In <i>SETDB1</i>-knockout hepatocytes, hypomethylation of DDX5 facilitates the formation of the DDX5-METTL3-METTL14 complex, increasing m⁶A modification of <i>BECN1</i> and <i>TFEB</i> mRNAs. This modification promoted YTHDF2-mediated decay of these transcripts, thereby inhibiting starvation-induced autophagy and lipophagy. Furthermore, administration of the SETDB1 activator <i>(R, R)</i>-59 significantly enhances lipophagy and attenuates starvation-induced hepatic steatosis. Collectively, our findings reveal a novel pathway in which SETDB1 deficiency drives m⁶A-mediated mRNA degradation to suppress lipophagy, thereby contributing to hepatic steatosis.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When tau stalls the lysosome: decoupling trafficking and degradation in autophagy.","authors":"Celeste M Karch, Farzaneh S Mirfakhar","doi":"10.1080/15548627.2026.2669685","DOIUrl":"https://doi.org/10.1080/15548627.2026.2669685","url":null,"abstract":"<p><p>Tauopathies are characterized by the accumulation of misfolded tau and lysosomal dysfunction, yet whether defects in the autophagy-lysosome pathway are causal or secondary remains unclear. Recent work using human iPSC-derived neurons harboring the MAPT p.R406W mutation demonstrates that pathogenic tau is sufficient to disrupt lysosomal function upstream of tau accumulation. Tau species are differentially processed within lysosomes, with phosphorylated tau retained at the lysosomal membrane, consistent with a barrier to efficient cargo processing. Importantly, pharmacologic activation of autophagy restores degradative capacity and reduces tau burden without rescuing lysosomal motility, suggesting that trafficking and degradation represent separable axes of lysosomal biology. These findings position tau as an active disruptor of proteostasis and define a degradative bottleneck that shares features with lysosomal storage disorders. Together, this work reframes autophagy dysfunction in tauopathy as a modular defect with distinct therapeutic entry points.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":14.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847352","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ROS-driven mitophagy arrest mediates the anti-glioblastoma activity of Molephantin.","authors":"Zhipeng Ling, Junliang Li, Guocai Wang, Yubo Zhang, Jun-Ping Pan","doi":"10.1080/15548627.2026.2668084","DOIUrl":"https://doi.org/10.1080/15548627.2026.2668084","url":null,"abstract":"<p><p>Mitophagy, the selective autophagic degradation of mitochondria, often acts as a pro-survival mechanism in tumor cells, including Glioblastoma (GBM), by clearing damaged mitochondria and mitigating oxidative stress. GBM is a highly aggressive brain tumor characterized by profound resistance to conventional therapies. Our recent study identified Molephantin (EM-5), a natural small molecule capable of crossing the blood-brain barrier, as a potent anti-GBM agent. Mechanistically, EM-5 triggers severe mitochondrial dysfunction and massive reactive oxygen species (ROS) production in GBM. Crucially, we discovered that EM-5 acts as a novel late-stage mitophagy inhibitor. It specifically blocks the fusion of mitophagosomes with lysosomes without affecting early autophagosome formation or lysosomal acidification. This ROS-driven fusion defect leads to the toxic accumulation of damaged mitochondria, thereby amplifying oxidative stress and driving GBM cells into apoptosis. Collectively, our work establishes that targeting late-stage mitophagy flux via ROS modulation is a valuable paradigm for the discovery and development of therapeutic agents against GBM.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-3"},"PeriodicalIF":14.3,"publicationDate":"2026-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847420","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RYR:ATP6V0A1 complexes couple ER-lysosome contact sites to dynamic autophagy control.","authors":"Jens Loncke, Manon Callens, Geert Bultynck, Tim Vervliet","doi":"10.1080/15548627.2026.2669981","DOIUrl":"https://doi.org/10.1080/15548627.2026.2669981","url":null,"abstract":"<p><p>Ryanodine receptors (RYRs) are ER-resident Ca² ⁺ -release channels enriched in excitable cells, including neurons. RYR hyperactivity is implicated in early pathogenesis of disorders such as Alzheimer's disease (AD), which is associated with impaired autophagy. We recently uncovered a mechanism linking RYR activity to lysosome availability for autophagy. RYRs localize to ER - lysosome contact sites via direct binding to ATP6V0A1, a V-ATPase subunit that also suppresses RYR-mediated Ca² ⁺ release. In human iPSC-derived cortical neurons, spontaneous RYR activity promotes lysosomal secretion, depleting the intracellular lysosomal pool and inhibiting autophagic flux. RYR inhibition promotes ER - lysosome contacts, limits lysosomal secretion, and restores lysosome availability for autophagosome fusion and cargo degradation (including APP). Conversely, disrupting the RYR:ATP6V0A1 interaction using a RYR-derived protein fragment serving as a \"decoy\" for ATP6V0A1 evokes RYR hyperactivity and stimulates lysosomal secretion. In this Punctum, we discuss how this RYR2:ATP6V0A1 \"contact-site hub\" may be perturbed in disease and highlight open questions on how lysosomes decode RYR-derived Ca² ⁺ signals.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction.","authors":"","doi":"10.1080/15548627.2026.2644019","DOIUrl":"https://doi.org/10.1080/15548627.2026.2644019","url":null,"abstract":"","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-7"},"PeriodicalIF":14.3,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The nuclear receptor ESRRA is a crucial regulator of acute kidney injury through inhibition of the lipophagy-ferroptosis axis.","authors":"Yuanting Yang, Xuying Zhu, Yan Fang, Jialin Li, Xinghua Shao, Shu Li, Haijiao Jin, Chaojun Qi, Zhenyuan Li, Leyi Gu, Shan Mou, Qisheng Lin, Zhaohui Ni","doi":"10.1080/15548627.2026.2665391","DOIUrl":"10.1080/15548627.2026.2665391","url":null,"abstract":"<p><p>Acute kidney injury (AKI) is a clinically significant syndrome characterized by a rapid decline in renal function, affecting over 50% of patients in intensive care units. Ferroptosis, a recently identified form of regulated cell death, is driven by iron-dependent lipid peroxidation and has been implicated in AKI pathogenesis. Emerging evidence suggests that lipophagy - a selective autophagic degradation of lipid droplets - potentiates ferroptosis, though the upstream regulatory mechanisms remain poorly understood. ESRRA (estrogen related receptor, alpha), a key transcriptional regulator of fatty acid metabolism and macroautophagy/autophagy, may play a critical role in this process. In this study, we identified ESRRA as a pivotal transcription factor in proximal tubular epithelial cells using single-cell transcriptomic analysis. To investigate its functional role, we employed wild-type mice and tubular epithelial cell-specific <i>Esrra</i> deficient mice to establish AKI models. Our findings demonstrated that ESRRA exerted a protective effect by modulating the RAB7-dependent lipophagy-ferroptosis axis. Furthermore, integrating chromatin Immunoprecipitation (ChIP)-seq and JASPAR database analyses, we predicted <i>PIK3CA</i> as a direct transcriptional target of ESRRA. Mechanistically, ESRRA bind to a specific promoter region within <i>Pik3ca</i>, enhancing its expression and subsequently activating the AKT-MTOR signaling pathway, which is required for the suppression of RAB7 mediated lipophagy in renal tubular epithelial cells, thereby attenuating AKI progression.<b>Abbreviations:</b> ACSL4: acyl-CoA synthetase long-chain family member 4; AKI: acute kidney injury; AKT/PKB: Akt serine/threonine kinase; ChIP: chromatin Immunoprecipitation; Cis-AKI: cisplatin-induced acute kidney injury; CI-AKI: contrast-induced acute kidney injury; ER: endoplasmic reticulum; ESRRA: estrogen related receptor, alpha; FFAs: free fatty acids; FA-AKI: folic acids-induced acute kidney injury; GPX4: glutathione peroxidase 4; GSH: glutathione; HK-2 cells: human renal proximal tubular epithelial cells; LDs: lipid droplets; LV: lentivirus; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; PPARGC1A/PGC1-α: PPARG coactivator 1 alpha; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha; PLIN2: perilipin 2; PNPLA2/ATGL: patatin-like phospholipase domain containing 2; PT: proximal tubular epithelial cells; PUFA: polyunsaturated fatty acid; RAB7: RAB7, member RAS oncogene family; ROS: reactive oxygen species; SQSTM1: sequestosome 1.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":"1-22"},"PeriodicalIF":14.3,"publicationDate":"2026-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147791953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRKN/parkin-mediated control of SNCA (synuclein alpha) and chaperone-mediated autophagy are defective in cellular, mice models and Parkinson disease-affected brains.","authors":"Lígia Ramos Dos Santos, Eric Duplan, Juliane Debord, Gwendoline Fremont, Julien Minniti, Inger Lauritzen, Eugenie Mutez, Coline Leghay, Marie Christine Chartier-Harlin, Frédéric Checler, Cristine Alves da Costa","doi":"10.1080/15548627.2026.2669458","DOIUrl":"https://doi.org/10.1080/15548627.2026.2669458","url":null,"abstract":"<p><p>Pathological accumulation of toxic SNCA species and loss of E3-ligase function of PRKN are two key features observed in Parkinson disease (PD). Here, we established the contribution of an E3-ligase-independent transcriptional function of PRKN in SNCA regulation. PRKN depletion decreased <i>SNCA</i> and <i>GBA1</i> (glucosylceramidase beta 1) mRNA levels and reduced CMA-driven degradation of SNCA, thereby triggering the accumulation of its phosphorylated aggregation-prone toxic species. We established that PRKN controls the CMA player LAMP2A but not HSPA8/HSC70 in isolated lysosomal fractions prepared from human neuronal and mouse fibroblastic cells. Further, we showed that PRKN-associated regulation of LAMP2 is isoform specific. We showed that PRKN-mediated control of SNCA, GBA1 and LAMP2A occurs <i>in vivo</i> and is impaired in the paraquat-treated PD mice model. We showed that the levels of phosphorylated SNCA and PRKN are correlated in sporadic PD human brain samples and that fibroblasts of patients carrying pathogenic <i>PRKN</i> mutations exhibit impaired CMA activity. Our study decrypts a new molecular mechanism linking three PD major therapeutic targets. It enriches the portfolio of transcriptional targets of PRKN and establishes PRKN as a novel CMA regulator. Further, it shows that PRKN controls both direct and indirect (GBA1-dependent) transcriptional regulation of <i>SNCA</i>. This novel molecular cascade opens potential new avenues in PD treatment.</p>","PeriodicalId":93893,"journal":{"name":"Autophagy","volume":" ","pages":""},"PeriodicalIF":14.3,"publicationDate":"2026-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147847427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}