Many human neurological diseases, including Parkinson's disease, Alzheimer's disease, and Huntington's disease, are associated with abnormal levels of protein buildup inside brain cells (neurons). A substantial body of evidence suggests that these abnormal protein aggregations somehow disrupt normal neuronal functions and eventually cause neuronal death. The protein that forms abnormal aggregations in PD, along with a few other disorders such as dementia with Lewy bodies and multiple system atrophy, is called alpha-synuclein, which is a normal part of neuronal physiology. Cells have protein breakdown machinery that helps prevent clumps of protein from building to toxic levels. Our laboratory has recently demonstrated that cells can indeed break down alpha-synuclein aggregates; it is presumed that this system is inadequate or fails altogether in PD neurons. The object of our study is to detail the mechanism by which cells remove toxic alpha-synuclein aggregates and to assess the protective effect of protein breakdown. We will specifically test the hypothesis that the toxic alpha-synuclein aggregates are degraded by the autophagic-lysosomal system, which is one of the major protein breakdown systems. Our long-term goal is to discover strategies to halt or prevent PD by means of clearing toxic alpha-synuclein aggregates.