C-elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging

van Ham, T.J., Thijssen, K.L., Breitling, R. , Hofstra, R.M.W., Plasterk, R.H.A. and Nollen, E.A.A. (2008) C-elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging. PLoS Genetics, 4(3), e1000027. (doi: 10.1371/journal.pgen.1000027)

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 <i>C-elegans</i> 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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Breitling, Professor Rainer
• Authors: van Ham, T.J., Thijssen, K.L., Breitling, R., Hofstra, R.M.W., Plasterk, R.H.A., and Nollen, E.A.A.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
• Journal Name: PLoS Genetics
• Publisher: Public Library of Science
• ISSN: 1553-7390
• ISSN (Online): 1553-7404
• Published Online: 21 March 2008
• Copyright Holders: Copyright © 2008 The Authors
• First Published: First published in PLoS Genetics 4(10):e1000232
• Publisher Policy: Reproduced in accordance with the copyright policy of the publisher.