Unknown

Dataset Information

0

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


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.

SUBMITTER: Bento CF 

PROVIDER: S-EPMC4906231 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Bento Carla F CF   Ashkenazi Avraham A   Jimenez-Sanchez Maria M   Rubinsztein David C DC  

Nature communications 20160609


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 c  ...[more]

Similar Datasets

| S-EPMC4517210 | biostudies-literature
| S-EPMC7940168 | biostudies-literature
| S-EPMC8673698 | biostudies-literature
| S-EPMC4014187 | biostudies-literature
| S-EPMC7731751 | biostudies-literature
| S-EPMC6410467 | biostudies-literature
| S-EPMC7723492 | biostudies-literature
| S-EPMC6379910 | biostudies-literature
| S-EPMC6170747 | biostudies-literature
| S-EPMC3386943 | biostudies-literature