Publication

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. & Nollen, E. A. A., 21-Mar-2008, In : PLoS genetics. 4, 3, 11 p., 1000027.

Research output: Contribution to journalArticleAcademicpeer-review

  • Tjakko J. van Ham
  • Karen L. Thijssen
  • Rainer Breitling
  • Robert M. W. Hofstra
  • Ronald H. A. Plasterk
  • Ellen A. A. Nollen

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.

Original languageEnglish
Article number1000027
Number of pages11
JournalPLoS genetics
Volume4
Issue number3
Publication statusPublished - 21-Mar-2008

    Keywords

  • ENVIRONMENTAL RISK-FACTORS, PARKINSONS-DISEASE, CAENORHABDITIS-ELEGANS, LEWY BODIES, LIFE-SPAN, DROSOPHILA MODEL, TOXICITY, AGGREGATION, DEMENTIA

Download statistics

No data available

ID: 4715995