VPS35 as a therapeutic target in Parkinson's disease

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Modified Project Summary/Abstract Section A key pathological feature of Parkinson disease (PD) is the accumulation of oligomeric and aggregated forms of alpha-synuclein (αSyn) in intracellular inclusions. VPS35 is a retromer subunit involved in multiple protein degradation pathways, including degradation of αSyn. Mutations in VPS35 are a cause of late-onset autosomal dominant PD. Lentiviral overexpression of VPS35 protein in the brain attenuates the accumulation of αSyn protein in αSyn transgenic mice. Given these converging data, we propose to pharmacologically increase levels of VPS35 as a potential disease-modifying strategy for PD. First, we aim to validate a novel therapeutic approach using pharmacological chaperones to target VPS35 in an αSyn based mouse model of PD. The pharmacological chaperones were selected for their ability to increase VPS35 levels in the brain of rodents. Our investigation started from studies of a pharmacological chaperone, R55, that stabilizes the retromer complex and increase VPS35 levels in cell lines by binding an active binding site between VPS39-VPS35 retromer subunits. We generated a small library of R55-inspired compounds designed to increase retromer stability and lipophilicity with greater blood brain barrier (BBB) penetration and we identified the lead compound, 1,3 phenyl bis-guanylhydrazone (2a). We assessed 2a efficacy in vitro in Neuro2A cells, in vivo in WT mice and in an Amyotrophic Lateral Sclerosis (ALS) mouse model. We have preliminary data demonstrating that our lead compound increases VPS35 levels in the substantia nigra in vivo. We now propose to test the ability of this compound in vivo to promote αSyn clearance and to assess its potential neuroprotective effects. We will assess for neuroprotection in the AAV-A53T-αSyn mouse model, and also will assess the roles of different αSyn clearance pathways in the protective effects of 2a through analyses in this mouse model as well as in neuronally differentiated SH-SY5Y neuroblastoma cells. The proposed studies will have important translational implications by providing key translational validation of this specific agent and more broadly of this novel therapeutic strategy.