Mutant ataxin-3 promotes the autophagic degradation of parkin.
There is growing evidence that autophagy plays a key role in neurodegenerative diseases. For instance, stimulating autophagy is neuroprotective both in vitro and in vivo in models of trinucleotide-repeat diseases such as Machado-Joseph disease (MJD). Similarly, proteins associated with familial forms of Parkinson disease (PD) such as parkin and PINK1 converge on the autophagy pathway. Yet, despite these shared mechanisms, it is not clear whether or how these disorders are related at a molecular level. We reported that the mutant form of ataxin-3, the protein responsible for MJD, promotes the autophagic degradation of parkin. Given that the loss of parkin function leads to PD, we propose that the increased turnover of parkin triggered by mutant ataxin-3 may explain some of the parkinsonian features observed in MJD. Moreover, the findings suggest that an increased clearance of parkin in MJD could mitigate the otherwise beneficial effects of autophagy in neurodegeneration.
Centre for Neuronal Survival and McGill Parkinson Program, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, QB, Canada. thomas.durcan@mail.mcgill.ca
Thomas M
TM
Durcan
Edward A
EA
Fon
D000818:Animals; D001343:Autophagy; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D017827:Machado-Joseph Disease / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D050505:Mutant Proteins / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D050505:Mutant Proteins; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D010450:Endopeptidases