Dorian Sargent, PhD Research & Impact Research Investigators Dorian Sargent, PhD Investigator: Dorian Sargent, PhD Name of Institution: Van Andel Research Institute, Grand Rapids, MI Project Title: Novel Molecular Mechanisms of VPS35-Linked Parkinson’s Disease: D620N VPS35 Knockin Mice Investigator Bio: Dr. Sargent is a post-doctoral fellow at the Van Andel Research Institute in Grand Rapids, Michigan. He earned a PharmD and an M.S. in molecular and cellular infectiology from the Philippe Maupas University of Tours, France and a PhD. in neuroscience from the Claude Bernard University of Lyon in France. Dr. Sargent is focused on the molecular mechanisms underlying Parkinson’s disease (PD) by studying proteins found mutated in familial cases of PD, such as Vacuolar Protein Sorting 35 ortholog (VPS35) and Leucine-Rich Repeat Kinase 2 (LRRK2). Objective: This project aims to identify the mechanisms by which a mutation of VPS35 implicated in some familial cases of PD induces neuronal death and protein accumulation in a VPS35 genetic mouse model of PD. It will also study the potential role of the LRRK2 protein in these processes. Background: VPS35 is a key component of the retromer complex, a large protein complex that is involved in transporting and recycling specific proteins. A mutation in the VPS35 gene has been identified as a cause of familial PD. How the mutation causes a change in the function of VPS35 or how it interferes with retromer formation are not well understood. A recent publication from our group reported that mutated VPS35 in a genetic mouse model can induce neuronal death and protein accumulation. In parallel, a recent publication also showed that mutated VPS35 could activate LRRK2, another protein implicated in familial PD, in this same mouse model. These studies suggest a novel interaction between VPS35 and LRRK2 that may induce neuropathology in the VPS35 mouse model. Interestingly, these mice develop abnormal accumulations of tau in the brain, and not a-synuclein suggesting that understanding VPS35 biology may also have ramifications for neurodegenerative diseases that accumulate tau such as progressive supranuclear palsy (PSP). Methods/Design: We will determine the brain regions and cell types in which LRRK2 is activated, using neuronal cultures and brain tissue of the VPS35 mouse model. We will study protein accumulation, neuron-to-neuron transmission of pathogenic proteins, and lysosomal pathway function in cultured neurons from these mice. Finally, the contribution of LRRK2 activity to these processes will be probed using selective LRRK2 inhibitors. Relevance to Diagnosis/Treatment of Parkinson’s disease: By understanding how VPS35 mutations contribute to the development of PD, we will better understand the general molecular mechanisms that lead to PD, which is fundamental to the development of new therapeutics for PD.