First Author | Bento CF | Year | 2016 |
Journal | Nat Commun | Volume | 7 |
Pages | 11803 | PubMed ID | 27278822 |
Mgi Jnum | J:239895 | Mgi Id | MGI:5881999 |
Doi | 10.1038/ncomms11803 | Citation | Bento CF, et al. (2016) The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway. Nat Commun 7:11803 |
abstractText | 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. |