Reference - Detail
| RRC ID | 4311 |
|---|---|
| Author | van Ham TJ, Thijssen KL, Breitling R, Hofstra RM, Plasterk RH, Nollen EA. |
| Title | C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging. |
| Journal | PLoS Genet |
| Abstract |
Inclusions in the brain containing alpha-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 alpha-synuclein inclusions. In worms of old age, inclusions contain aggregated alpha- 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 alpha-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 alpha-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 alpha-synuclein related disorders. |
| Volume | 4(3) |
| Pages | e1000027 |
| Published | 2008-3-21 |
| DOI | 10.1371/journal.pgen.1000027 |
| PMID | 18369446 |
| PMC | PMC2265412 |
| MeSH | Aging / genetics* Aging / metabolism* Animals Animals, Genetically Modified Bacterial Proteins / genetics Bacterial Proteins / metabolism Base Sequence Brain / metabolism Caenorhabditis elegans / genetics* Caenorhabditis elegans / metabolism* DNA Primers / genetics Fluorescence Recovery After Photobleaching G-Protein-Coupled Receptor Kinases / antagonists & inhibitors G-Protein-Coupled Receptor Kinases / genetics G-Protein-Coupled Receptor Kinases / metabolism Gene Deletion Genes, Helminth Humans Inclusion Bodies / metabolism* Luminescent Proteins / genetics Luminescent Proteins / metabolism Models, Genetic Parkinson Disease / etiology Parkinson Disease / genetics Parkinson Disease / metabolism RNA Interference Recombinant Fusion Proteins / genetics Recombinant Fusion Proteins / metabolism alpha-Synuclein / antagonists & inhibitors alpha-Synuclein / genetics* alpha-Synuclein / metabolism* |
| IF | 5.175 |
| Times Cited | 231 |
| WOS Category | GENETICS & HEREDITY |
| Resource | |
| C.elegans | tm1920 |