A Caenorhabditis elegans Parkin mutant with altered solubility couples alpha-synuclein aggregation to proteotoxic stress.
Mutations in the human parkin gene encoding an E3 ubiquitin ligase have been associated with early-onset recessive forms of Parkinson's disease (PD). However, the molecular mechanisms by which mutations in the parkin gene cause PD are still under debate. Here, we identified and characterized the Caenorhabditis elegans parkin homolog, pdr-1. PDR-1 protein physically associates and cooperates with a conserved degradation machinery to mediate ubiquitin conjugation. Strikingly, in contrast to pdr-1 loss-of-function mutants, an in-frame deletion variant with altered solubility and intracellular localization properties is hypersensitive toward different proteotoxic stress conditions. Both endoplasmic reticulum-derived folding stress and cytosolic stress conferred by expression of mutant human alpha-synuclein resulted in severe developmental defects and lethality in pdr-1(lg103) mutant background. Furthermore, we show that the corresponding truncated protein PDR-1(Deltaaa24-247) aggregates in cell culture, but still interacts with its ubiquitylation co-enzymes. Thus, it might block the cellular degradation/detoxification machinery and therefore renders worms highly vulnerable to protein folding stress. In contrast to other complete gene knockouts or RNAi models of Parkin function, this C. elegans model recapitulates Parkin insolubility and aggregation similar to several autosomal recessive juvenile parkinsonism (AR-JP)-linked Parkin mutations. We suggest that such Parkin variants that either confer a neomorphic function or a partial loss-of-function may help to further elucidate the biological function of Parkin in vivo and the pathogenic mechanisms resulting in AR-JP. Due to high-throughput capacity of C. elegans, this model is particularly well suited to identify genetic and chemical modifiers of toxicity.
Springer
Wolfdieter
W
ABI/Molecular Neurogenetics, University of Munich, Germany.
Hoppe
Thorsten
T
Schmidt
Enrico
E
Baumeister
Ralf
R
D000595:Amino Acid Sequence; D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000502:physiology; D019656:Loss of Heterozygosity / Q000235:genetics; D008969:Molecular Sequence Data; D018384:Oxidative Stress / Q000235:genetics*; D017384:Sequence Deletion; D012995:Solubility; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
D029742:Caenorhabditis elegans Proteins; D025801:Ubiquitin; D051844:alpha-Synuclein; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein