Paper: New paper from the Rubinsztein Group – Autophagy regulation by Parkinson’s disease-associated genes
In this recent paper from David Rubinsztein’s lab, the authors decipher the molecular mechanisms underlying the regulation of autophagy and lysosomal functions by the Parkinson’s disease-associated genes ATP13A2 and SYT11.
Mutations of the ATP13A2 gene – encoding a lysosomal P5-type ATPase – have been associated to some forms of early-onset Parkinsonism. These mutations that deplete ATP13A2 protein from the lysosome induce lysosomal dysfunction and impaired degradation of autophagosomes and α-synuclein. Identified from genome-wide association studies, Synaptotagmin-11 (SYT11) has emerged as a potential Parkinson’s disease-associated gene. SYT11 belongs to a family of proteins involved in vesicle fusion, trafficking and exocytosis. Here the authors show that ATP13A2 regulates SYT11 expression at both transcriptional and post-translational levels.
Transcriptional regulation of SYT11 expression by ATP13A2 involves the TSC2/mTORC1/TFEB pathway. It is shown that ATP13A2 depletion results in the activation of MYCBP2 ubiquitin ligase activity towards the mTORC1 negative regulator TSC2. In an active state, mTORC1 phosphorylates the transcription factor EB (TFEB) impairing its translocation to the nucleus and thus its binding SYT11 promoter.
In parallel, ATP13A2 positively regulates SYT11 protein stability. Indeed, ATP13A2 depletion is associated with increased ubiquitination levels and proteosomal degradation of SYT11.
Knockdowns of ATP13A2 and SYTT11 both block autophagosome clearance and compromise lysosomal function (increased lysosomal pH and decreased levels and activity of Cathepsin-L) in a very similar extent, suggesting that they act in a common pathway. Interestingly, exogenous expression of SYT11 rescues the autophagic flux inhibition observed after ATP13A2 knockdown. This suggests that impairment of autophagy and lysosomal function associated with ATP13A2 depletion is dependent on SYT11.
Defects in this proposed ATP13A2/SYT11 network are likely to contribute to lysosomal dysfunction, autophagy blockage and impairment of α-synuclein clearance associated with Parkinson’s disease.
To learn more:
The Parkinson’s disease-associated genes ATP13A2 and SYT11 regulate autophagy via a common pathway. Nat Commun. 2016 Jun 9;7:11803. (PMID :27278822)