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 first reporting period we have made great progress in developing novel methods to probe the autophagy pathway in single cells. This pathway is involved in the turnover of misfolded proteins and dysfunction organelles. Using our novel autophagy assays, we have preliminary data that indicate that the autophagy pathway in neurons from HD patients is modulated compared to healthy controls. We have also begun validating small molecules that activate the autophagy pathway and we are now moving these inducers into human neurons from HD patients to see if they reduce toxicity or other disease related phenotypes. Using pathway analysis we have also identified specific genes within the proteostasis network that are modulated in HD. We are now testing whether modulating these genes in human neurons from HD patients can lead to a reduction in neurodegeneration. In the final part of this study we are investigating whether neurodegenerative diseases, such as HD and PD, share changes in similar genes or pathways, specifically those involved in protein homeostasis. We have now established a human neuron model for PD and have used it to identify potential targets that modulate the disease phenotype via changes in proteostasis. Using the assays, autophagy drugs and pathway analysis described above, we hope to identify overlapping targets that could potentially rescue disease associated phenotypes in both HD and PD.