Journal
NATURE COMMUNICATIONS
Volume 7, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/ncomms11803
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Funding
- Wellcome Trust [095317/Z/11/Z]
- Wellcome Trust/MRC Strategic Award in Neurodegeneration
- Wellcome Trust Strategic Grant [100140/Z/12/Z]
- Addenbrooke's Charitable Trust
- FEBS
- Medical Research Council [MC_G1000734] Funding Source: researchfish
- Wellcome Trust [095317/Z/11/Z, 100140/Z/12/Z] Funding Source: Wellcome Trust
- MRC [MC_G1000734] Funding Source: UKRI
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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.
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