The goal of our study is to identify common mechanisms that cause the degeneration of neurons and lead to most neurodegenerative disorders. Our work focuses on the protein homeostasis pathways that are disrupted in many forms of neurodegeneration, including Huntington’s disease (HD) and Parkinson’s disease (PD). In this reporting period we have made good progress in both developing new assays and novel autophagy compounds and identifying potential genetic targets that could lead to novel therapeutic strategies for patients with HD and PD. We have developed methods to measure the degradation rates of proteins involved in causing neurodegeneration and the decay rates of mitochondria that are disrupted during the progression of these diseases. We are now investigating if and how these degradation rates differ in cells from patients with HD. We have developed novel compounds that can activate the autophagy pathway which is critical for degrading the toxic proteins that cause neurodegeneration. We are now testing if these compounds can increase the survival of neurons derived from iPSCs from patients with HD. Using pathway analysis we have also identified specific genes within the proteostasis network that are modulated in HD. Specifically we have identified deubiquitinating enzymes as modulators of HD induced toxicity and autophagy modulation, potentially indicating that importance of the autophagy pathway in the disease progression. We are also using RNAseq analysis to investigate if neurons derived from iPSCs from PD patients exhibit differences in the genes expressed in the proteostasis network. If we identify key genes we will use our established human neuron model for PD to validate whether these genes modulate the disease phenotype via changes in proteostasis. Ultimately we hope to identify overlapping targets that could potentially rescue disease associated phenotypes in both HD and PD.