The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway

Carla F. Bento, Avraham Ashkenazi, Maria Jimenez-Sanchez, David C. Rubinsztein

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number11803
JournalNature Communications
Volume7
DOIs
StatePublished - 9 Jun 2016
Externally publishedYes

Fingerprint

Dive into the research topics of 'The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway'. Together they form a unique fingerprint.

Cite this