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Published on: April 4, 2018
Familial Parkinson's disease-associated L166P mutation disrupts DJ-1 protein folding and function
James A Olzmann1, Keith Brown, Keith D Wilkinson
1Departments of Pharmacology, Biochemistry, and Neurology, Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, Georgia 30322-3090, USA.
Abstract:
Mutations in DJ-1, a protein of unknown function, were recently identified as the cause for an autosomal recessive, early onset form of familial Parkinson's disease. Here we report that DJ-1 is a dimeric protein that exhibits protease activity but no chaperone activity. The protease activity was abolished by mutation of Cys-106 to Ala, suggesting that DJ-1 functions as a cysteine protease. Our studies revealed that the Parkinson's disease-linked L166P mutation impaired the intrinsic folding propensity of DJ-1 protein, resulting in a spontaneously unfolded structure that was incapable of forming a homodimer with itself or a heterodimer with wild-type DJ-1. Correlating with the disruption of DJ-1 structure, the L166P mutation abolished the catalytic function of DJ-1. Furthermore, as a result of protein misfolding, the L166P mutant DJ-1 was selectively polyubiquitinated and rapidly degraded by the proteasome. Together these findings provide insights into the molecular mechanism by which loss-of-function mutations in DJ-1 lead to Parkinson's disease.
Insights
Mutations in the DJ-1 protein cause early-onset Parkinson's disease. This study reveals DJ-1 acts as a cysteine protease, and the L166P mutation disrupts its structure and function, leading to disease.
Area of Science:
- Biochemistry
- Neuroscience
- Genetics
Background:
- Mutations in DJ-1 are linked to autosomal recessive, early-onset familial Parkinson's disease.
- The precise function of DJ-1 protein has remained largely unknown.
- Understanding DJ-1's role is crucial for elucidating Parkinson's disease pathogenesis.
Purpose of the Study:
- To investigate the biochemical function and structural properties of DJ-1 protein.
- To elucidate the molecular mechanism by which Parkinson's disease-linked mutations in DJ-1 lead to neurodegeneration.
Main Methods:
- Biochemical assays to assess protease and chaperone activity.
- Site-directed mutagenesis (Cys-106 to Ala, L166P mutation).
- Protein structural analysis, dimerization studies, ubiquitination assays, and proteasomal degradation studies.
Main Results:
- DJ-1 functions as a dimeric cysteine protease, with activity dependent on Cys-106.
- The L166P mutation disrupts DJ-1's folding, preventing dimerization and abolishing protease activity.
- Misfolded L166P mutant DJ-1 is polyubiquitinated and degraded by the proteasome.
Conclusions:
- DJ-1's function as a cysteine protease is essential for preventing Parkinson's disease.
- Loss-of-function mutations, like L166P, cause protein misfolding, loss of catalytic activity, and subsequent degradation, leading to disease.
- These findings provide critical insights into the molecular basis of DJ-1-associated Parkinson's disease.
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