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

Carla F. Bento, Avraham Ashkenazi, Maria Jimenez-Sanchez and David C. Rubinsztein ()
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Carla F. Bento: Cambridge Institute for Medical Research (CIMR)
Avraham Ashkenazi: Cambridge Institute for Medical Research (CIMR)
Maria Jimenez-Sanchez: Cambridge Institute for Medical Research (CIMR)
David C. Rubinsztein: Cambridge Institute for Medical Research (CIMR)

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11803

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