دورية أكاديمية
Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation
العنوان: | Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation |
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المؤلفون: | van der Welle, Reini E. N., Jobling, Rebekah, Burns, Christian, Sanza, Paolo, van der Beek, Jan A., Fasano, Alfonso, Chen, Lan, Zwartkruis, Fried J., Zwakenberg, Susan, Griffin, Edward F., ten Brink, Corlinda, Veenendaal, Tineke, Liv, Nalan, van Ravenswaaij-Arts, Conny M. A., Lemmink, Henny H., Pfundt, Rolph, Blaser, Susan, Sepulveda, Carolina, Lozano, Andres M., Yoon, Grace, Santiago-Sim, Teresa, Asensio, Cedric S., Caldwell, Guy A., Caldwell, Kim A., Chitayat, David, Klumperman, Judith |
المصدر: | van der Welle , R E N , Jobling , R , Burns , C , Sanza , P , van der Beek , J A , Fasano , A , Chen , L , Zwartkruis , F J , Zwakenberg , S , Griffin , E F , ten Brink , C , Veenendaal , T , Liv , N , van Ravenswaaij-Arts , C M A , Lemmink , H H , Pfundt , R , Blaser , S , Sepulveda , C , Lozano , A M , Yoon , G , Santiago-Sim , T , .... |
سنة النشر: | 2021 |
المجموعة: | University of Groningen research database |
مصطلحات موضوعية: | Autophagy, HOPS complex, lysosome‐, associated disorder, mTORC1, TFEB, TFE3 |
الوصف: | Vacuolar protein sorting 41 (VPS41) is as part of the Homotypic fusion and Protein Sorting (HOPS) complex required for lysosomal fusion events and, independent of HOPS, for regulated secretion. Here, we report three patients with compound heterozygous mutations in VPS41 (VPS41(S285P) and VPS41(R662)*; VPS41(c.1423-2A>G) and VPS41(R662)*) displaying neurodegeneration with ataxia and dystonia. Cellular consequences were investigated in patient fibroblasts and VPS41-depleted HeLa cells. All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo. By contrast, VPS41(S285P) enabled regulated secretion. Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation. Phosphorylation of mTORC1 substrates S6K1 and 4EBP1 was not affected. In a C. elegans model of Parkinson's disease, co-expression of VPS41(S285P)/VPS41(R662)* abolished the neuroprotective function of VPS41 against alpha-synuclein aggregates. We conclude that the VPS41 variants specifically abrogate HOPS function, which interferes with the TFEB/TFE3 axis of mTORC1 signaling, and cause a neurodegenerative disease. |
نوع الوثيقة: | article in journal/newspaper |
وصف الملف: | application/pdf |
اللغة: | English |
العلاقة: | https://research.rug.nl/en/publications/804b4fc8-bfe6-4f3c-9e8e-fc8c8471c83eTest |
DOI: | 10.15252/emmm.202013258 |
الإتاحة: | https://doi.org/10.15252/emmm.202013258Test https://hdl.handle.net/11370/804b4fc8-bfe6-4f3c-9e8e-fc8c8471c83eTest https://research.rug.nl/en/publications/804b4fc8-bfe6-4f3c-9e8e-fc8c8471c83eTest https://pure.rug.nl/ws/files/169776411/Neurodegenerative_VPS41_variants_inhibit_HOPS_function_and_mTORC1_dependent_TFEB_TFE3_regulation.pdfTest |
حقوق: | info:eu-repo/semantics/openAccess |
رقم الانضمام: | edsbas.9A64752A |
قاعدة البيانات: | BASE |
DOI: | 10.15252/emmm.202013258 |
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