c. elegans model identifies genetic modifiers of α-synuclein inclusion formation during aging秀丽隐杆线虫模型识别α-synuclein夹杂物形成的遗传修饰符在衰老.pdf

C. elegans Model Identifies Genetic Modifiers of a- Synuclein Inclusion Formation During Aging 1 1 2 1 3 Tjakko J. van Ham , Karen L. Thijssen , Rainer Breitling , Robert M. W. Hofstra , Ronald H. A. Plasterk , Ellen A. A. Nollen1* 1 Department of Genetics, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands, 2 Groningen Bioinformatics Centre, University of Groningen, Haren, The Netherlands, 3 Hubrecht Laboratory, Netherlands Institute of Developmental Biology, Utrecht, The Netherlands Abstract Inclusions in the brain containing a-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 a-synuclein inclusions. In worms of old age, inclusions contain aggregated a- 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 a-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 a-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 p