The lack of disease-modifying therapies is a crucial deficiency in the treatment of Parkinson disease (PD). Using cellular models of PD, we have identified the protein GADD34 as a novel potential therapeutic target to delay neurodegeneration. An FDA-approved drug, guanabenz, blocks GADD34 function and promotes cell survival. In this proposal, our goal is to evaluate GADD34 inhibition as a neuroprotective strategy to slow disease progression in PD. To do this, we will evaluate the effect of GADD34 inhibition on neurodegeneration in a well-established pre-clinical model of PD (injection of the toxin 6-hydroxydopamine). We will manipulate GADD34 function in two ways: genetically, by using models that lack the gene encoding GADD34, or pharmacologically, using guanabenz. Finally, we will assess second-generation guanabenz analogs in cellular PD models to identify promising candidates for future testing. If successful, our studies will provide strong evidence supporting further development of GADD34 blockade and guanabenz, specifically, as disease-modifying treatments for PD. Future studies will test the effect of GADD34 inhibition in a distinct pre-clinical model of PD, such as alpha-synuclein (protein associated with PD) overexpression. Since guanabenz is an FDA-approved drug, positive results have the potential to be rapidly advanced to clinical trials.