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Public Library of Science, PLoS Genetics, 3(4), p. e1000027, 2008

DOI: 10.1371/journal.pgen.1000027

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

Journal article published in 2008 by Tjakko J. van Ham, Karen L. Thijssen, Rainer Breitling ORCID, Robert M. W. Hofstra, Ronald H. A. Plasterk, Ellen A. A. Nollen
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Inclusions in the brain containing ??-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 ??-synuclein inclusions. In worms of old age, inclusions contain aggregated ??-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 ??-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 ??-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 ??-synuclein related disorders.?? 2008 van Ham et al.