Protein misfolding is a fundamental problem in biology which is associated with several neurodegenerative disorders, such as Parkinson’s, Alzheimer’s, Huntington’s, and Prion diseases. The overall goal of my research will be to contribute for the understanding of how protein misfolding is associated with disease. Therefore, my research will be focused on the identification and characterization of the toxic species leading to neurotoxicity in different neurodegenerative disorders. This knowledge is critical for a thorough understanding of the disease mechanisms. I will also focus on determining the normal function and biology of some of the key proteins involved in these diseases, such as -synuclein, DJ-1, Tau, and huntingtin, to elucidate how each protein relates to the pathobiology of the respective disease. In HD, for example, recent evidence suggests that loss of normal huntingtin function is involved in the disease mechanisms. In PD, the recessive nature of some of the mutations associated with familial cases also suggests that loss of function might be at the root of the problems. For my research I will employ advanced molecular and cell biology tools, such as genetic screens in yeast and RNA interference screens in mammalian cells, coupled to other genomic approaches, such as gene profiling experiments. I will couple these lines of investigation with novel in vitro and in vivo imaging approaches for the study of protein misfolding at a molecular level, with the ultimate goal of discovering novel avenues for therapeutic intervention.