C-elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during agingvan Ham, T. J., Thijssen, K. L., Breitling, R., Hofstra, R. M. W., Plasterk, R. H. A. & Nollen, E. A. A., 21-Mar-2008, In : PLoS genetics. 4, 3, 11 p., 1000027.
Research output: Contribution to journal › Article › Academic › peer-review
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.
|Number of pages||11|
|Publication status||Published - 21-Mar-2008|
- ENVIRONMENTAL RISK-FACTORS, PARKINSONS-DISEASE, CAENORHABDITIS-ELEGANS, LEWY BODIES, LIFE-SPAN, DROSOPHILA MODEL, TOXICITY, AGGREGATION, DEMENTIA