{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Bento CF"],"funding":["Medical Research Council","Wellcome Trust"],"pagination":["11803"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC4906231"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["7"],"pubmed_abstract":["Forms of Parkinson's disease (PD) are associated with lysosomal and autophagic dysfunction. ATP13A2, which is mutated in some types of early-onset Parkinsonism, has been suggested as a regulator of the autophagy-lysosome pathway. However, little is known about the ATP13A2 effectors and how they regulate this pathway. Here we show that ATP13A2 depletion negatively regulates another PD-associated gene (SYT11) at both transcriptional and post-translational levels. Decreased SYT11 transcription is controlled by a mechanism dependent on MYCBP2-induced ubiquitination of TSC2, which leads to mTORC1 activation and decreased TFEB-mediated transcription of SYT11, while increased protein turnover is regulated by SYT11 ubiquitination and degradation. Both mechanisms account for a decrease in the levels of SYT11, which, in turn, induces lysosomal dysfunction and impaired degradation of autophagosomes. Thus, we propose that ATP13A2 and SYT11 form a new functional network in the regulation of the autophagy-lysosome pathway, which is likely to contribute to forms of PD-associated neurodegeneration."],"journal":["Nature communications"],"pubmed_title":["The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway."],"pmcid":["PMC4906231"],"funding_grant_id":["MC_G1000734","100140/Z/12/Z"],"pubmed_authors":["Bento CF","Rubinsztein DC","Ashkenazi A","Jimenez-Sanchez M"],"additional_accession":[]},"is_claimable":false,"name":"The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway.","description":"Forms of Parkinson's disease (PD) are associated with lysosomal and autophagic dysfunction. ATP13A2, which is mutated in some types of early-onset Parkinsonism, has been suggested as a regulator of the autophagy-lysosome pathway. However, little is known about the ATP13A2 effectors and how they regulate this pathway. Here we show that ATP13A2 depletion negatively regulates another PD-associated gene (SYT11) at both transcriptional and post-translational levels. Decreased SYT11 transcription is controlled by a mechanism dependent on MYCBP2-induced ubiquitination of TSC2, which leads to mTORC1 activation and decreased TFEB-mediated transcription of SYT11, while increased protein turnover is regulated by SYT11 ubiquitination and degradation. Both mechanisms account for a decrease in the levels of SYT11, which, in turn, induces lysosomal dysfunction and impaired degradation of autophagosomes. Thus, we propose that ATP13A2 and SYT11 form a new functional network in the regulation of the autophagy-lysosome pathway, which is likely to contribute to forms of PD-associated neurodegeneration.","dates":{"release":"2016-01-01T00:00:00Z","publication":"2016 Jun","modification":"2024-11-19T23:06:34.85Z","creation":"2019-03-27T02:15:57Z"},"accession":"S-EPMC4906231","cross_references":{"pubmed":["27278822"],"doi":["10.1038/ncomms11803"]}}