The Parkinson's disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway.
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.
Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), Wellcome/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
Carla F
CF
Bento
Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), Wellcome/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
Avraham
A
Ashkenazi
Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), Wellcome/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
Maria
M
Jimenez-Sanchez
Department of Medical Genetics, Cambridge Institute for Medical Research (CIMR), Wellcome/MRC Building, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
David C
DC
Rubinsztein
D001343:Autophagy; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000235:genetics / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics*; D006180:Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D050857:Synaptotagmins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
C514983:ATP13A2 protein, human; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D012333:RNA, Messenger; C494265:SYT11 protein, human; C064972:TFEB protein, human; D050857:Synaptotagmins; D000076222:Mechanistic Target of Rapamycin Complex 1; D006180:Proton-Translocating ATPases