C. elegans Model Identifies Genetic Modifiers of ??-Synuclein Inclusion Formation During Aging |
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| Authors: | Tjakko J van Ham Karen L Thijssen Rainer Breitling Robert M W Hofstra Ronald H A Plasterk Ellen A A Nollen |
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| Institution: | 1Department of Genetics, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands;2Groningen Bioinformatics Centre, University of Groningen, Haren, The Netherlands;3Hubrecht Laboratory, Netherlands Institute of Developmental Biology, Utrecht, The Netherlands;Stanford University Medical Center, United States of America |
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| 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. |
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