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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

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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]

PMID: 27278822

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Project description:Parkinson's disease (PD) can lead to movement injury and cognitive dysfunction. Although advances have been made in attenuating PD, the effect of inhibiting the development of PD remains disappointing. Therefore, the present study aimed at investigating the etiology of Parkinson's disease and developing an alternative therapeutic strategy for patients with PD. A PD mouse model was established using an intraperitoneal injection of 1‑methyl‑4‑phenyl‑1,2,3,6‑tetrahydropyridine hydrochloride (MPTP‑HCl; 30 mg/kg/day for 5 days), and a PD cellular model was established by treating SH‑SY5Y cells with different concentrations of 1‑methyl‑4‑phenylpyridinium (MPP+) for 24 h. The expression levels of circular RNA sterile α motif domain containing 4A (circSAMD4A) and microRNA (miR)‑29c‑3p in both midbrain tissues and SH‑SY5Y cells were detected via reverse transcription‑quantitative PCR. The interaction between circSAMD4A and miR‑29c‑3p was verified using a dual‑luciferase reporter experiment. Apoptosis‑, autophagy‑ and 5'AMP‑activated protein kinase (AMPK)/mTOR cascade‑associated proteins in midbrain tissues and SH‑SY5Y cells were detected using western blotting. Furthermore, TUNEL staining and flow cytometry were used to analyze cell apoptosis. It was found that circSAMD4A was upregulated, while miR‑29c‑3p was downregulated in both PD animal and cellular models. Moreover, circSAMD4A directly targeted and negatively regulated miR‑29c‑3p. Further studies identified that circSAMD4A knockdown inhibited MPTP‑ or MPP+‑induced apoptosis and autophagy; however, these effects were abolished by an miR‑29c‑3p inhibitor. In addition, circSAMD4A knockdown repressed phosphorylated‑AMPK expression and increased mTOR expression in MPTP‑ or MPP+‑induced PD models, the effects of which were reversed by a miR‑29c‑3p inhibitor. Collectively, these results suggested that circSAMD4A participated in the apoptosis and autophagy of dopaminergic neurons by modulating the AMPK/mTOR cascade via miR‑29c‑3p in PD.

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

Publications

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

Similar Datasets

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