C. elegans model identifies genetic modifiers of alpha-synuclein inclusion formation during aging.
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.
van Ham
Tjakko J
TJ
Department of Genetics, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands.
Thijssen
Karen L
KL
Breitling
Rainer
R
Hofstra
Robert M W
RM
Plasterk
Ronald H A
RH
Nollen
Ellen A A
EA
D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D036681:Fluorescence Recovery After Photobleaching; D054768:G-Protein-Coupled Receptor Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D017238:Genes, Helminth; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008957:Models, Genetic; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D051844:alpha-Synuclein / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*
D001426:Bacterial Proteins; D017931:DNA Primers; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D051844:alpha-Synuclein; C054562:yellow fluorescent protein, Bacteria; D054768:G-Protein-Coupled Receptor Kinases