C. elegans Model Identifies Genetic Modifiers of α-Synuclein Inclusion Formation During Aging
Open Access
- 21 March 2008
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLoS Genetics
- Vol. 4 (3), e1000027
- https://doi.org/10.1371/journal.pgen.1000027
Abstract
Inclusions in the brain containing α-synuclein are the pathological hallmark of Parkinson's disease, but how these inclusions are formed and how this links to disease is poorly understood. We have developed a C. elegans model that makes it possible to monitor, in living animals, the formation of α-synuclein inclusions. In worms of old age, inclusions contain aggregated α- synuclein, resembling a critical pathological feature. We used genome-wide RNA interference to identify processes involved in inclusion formation, and identified 80 genes that, when knocked down, resulted in a premature increase in the number of inclusions. Quality control and vesicle-trafficking genes expressed in the ER/Golgi complex and vesicular compartments were overrepresented, indicating a specific role for these processes in α-synuclein inclusion formation. Suppressors include aging-associated genes, such as sir-2.1/SIRT1 and lagr-1/LASS2. Altogether, our data suggest a link between α-synuclein inclusion formation and cellular aging, likely through an endomembrane-related mechanism. The processes and genes identified here present a framework for further study of the disease mechanism and provide candidate susceptibility genes and drug targets for Parkinson's disease and other α-synuclein related disorders. Parkinson's disease is the second most common brain disorder of the elderly. It is thought to be caused by environmental and genetic factors. However, little is known about the genes and processes involved. Pathologically, Parkinson's disease is recognized by inclusions in the brain that contain a disease-specific protein: alpha-synuclein. We created a small animal model (C. elegans) in which we could follow the formation of alpha-synuclein inclusions in living and aging animals. With a genome-wide RNAi screen we identified 80 genes whose expression influences inclusion formation. These genes include evolutionarily conserved regulators of longevity, suggesting a link between inclusion formation and the molecular mechanism of aging. Our results offer a refined understanding of how Parkinson's disease arises during aging and we identify processes and genes that may underlie an increased susceptibility for the disease, which is important for improving diagnostics and developing strategies for therapeutic intervention.Keywords
This publication has 32 references indexed in Scilit:
- The Parkinson's disease protein α-synuclein disrupts cellular Rab homeostasisProceedings of the National Academy of Sciences, 2008
- Yeast Genes That Enhance the Toxicity of a Mutant Huntingtin Fragment or α-SynucleinScience, 2003
- α-Synuclein Locus Triplication Causes Parkinson's DiseaseScience, 2003
- Polyglutamine protein aggregates are dynamicNature, 2002
- The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegansProceedings of the National Academy of Sciences, 2002
- Lipid Droplet Binding and Oligomerization Properties of the Parkinson's Disease Protein α-SynucleinJournal of Biological Chemistry, 2002
- Chaperone Suppression of α-Synuclein Toxicity in a Drosophila Model for Parkinson's DiseaseScience, 2002
- Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegansNature, 2001
- Stress management – heat shock protein-70 and the regulation of apoptosisTrends in Cell Biology, 2001
- The zyxin-related protein TRIP6 interacts with PDZ motifs in the adaptor protein RIL and the protein tyrosine phosphatase PTP-BLEuropean Journal of Cell Biology, 2000