C. elegans paper by Tjakko van Ham published in PLoS Genetics

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.

C. elegans Model Identifies Genetic Modifiers of α -Synuclein Inclusion Formation During Aging

Tjakko J. van Ham, Karen L. Thijssen, Rainer Breitling, Robert M. W. Hofstra, Ronald H. A. Plasterk, Ellen A. A. Nollen

Summary

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.

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A response to this paper can be found at http://www.alzforum.org/new/detail.asp?id=1780

More information about the work on C. elegans being performed in the Genetics Department can be found here.