SCIENCE UP THE WORLD
15TH INTERNATIONAL STUDENT CONGRESS OF MEDICAL SCIENCES
JUNE 3RD - 6TH 2008
Ellen A.A. Nollen
C. elegans models for human neurodegenerative diseasesTjakko van Ham1, Karen Thijssen1, Ronald Plasterk2 & Ellen Nollen1 1 UMCG, Department of Genetics, Groningen, The Netherlands, 2Division of Functional Genomics, Hubrecht Laboratories, Utrecht, The Netherlands Aggregation of misfolded proteins occurs in various age-related neurodegenerative disorders, including Parkinson’s, Alzheimer’s, and Huntington’s disease. To understand how cells protect themselves against misfolded proteins, we search for genes that enhance or prevent age-dependent protein aggregation. We have recently created a genetic C. elegans model for Parkinson’s disease, which captures several features of Parkinson’s disease and other synucleopathies. This includes the age-dependent accumulation and immobilization of misfolded alpha-synuclein in microscopically visible foci and disease specific phosphorylation of alpha-synuclein at serine 129. We have performed a genome-wide RNAi screen for modifiers of alpha-synuclein foci-formation and identified genes that enhanced or suppress foci-formation after knock down by RNAi, most of which have human orthologues. These include genes encoding proteins that have been found by others to associate with Lewy-bodies, the aggregates in Parkinson’s disease. Previously, we have identified genes that, when knocked down, cause premature protein aggregation in a C.elegans model for polyglutamine aggregation. Within this set are genes involved in protein synthesis, folding, degradation and RNA synthesis and processing. Interestingly, although some of the major functional classes that have been previously picked up as suppressors of polyglutamine aggregation modify foci formation of alpha-synclein as well, none of the genes identified overlap. This suggests that cells use multiple and different sets of genes to handle different misfolded proteins. Altogether our results will provide insight into cellular protection against misfolded proteins and yield targets for therapy against Parkinson’s disease and other protein misfolding disorders.
