Grant: Project Grant

Parkinson's disease, Lewy body dementia and related disorders all have one feature in common: an abnormally accumulated protein called alpha-synuclein (a-syn). Though two decades of research have provided insight into how a-syn accumulates in cells, very little is known about how and why it is toxic to the cell. This has consequently slowed therapeutic development, largely due to a paucity in animal models. Specifically, the question of why a normally abundant brain-resident protein becomes toxic over time remains enigmatic. Work from our lab and others has suggested that the toxic misplacement, or mislocalization of a-syn to the nucleus is a contributor to the pathogenic process. As a result, our lab recently made new mouse models to study: 1) what factors cause a-syn to mislocalize, and 2) whether constitutively forcing a-syn into the nucleus causes features reminiscent of PD in mice. In the first case, we found that a-syn interacts with another Parkinson's related protein called Synaptojanin 1 (Synj1), and that disruption of this interaction results in features reminiscent of early PD. In the second mouse line, we found that we were able to target a-syn to the cell's nucleus and that these mice, even at an early age, begin to exhibit motor deficits. Building on this foundational data, this proposal aims to look at the interplay between both proteins and will capitalize on this genetic interaction to: 1) Determine the contribution of the a-syn-Synj1 protein interaction to PD in mice and humans; and 2) Generate novel preclinical mouse models of this disease that can be used for pharmacological testing down the line. At the end of this study, we will be able place the toxicity of nuclear a-syn as a key facet of disease, creating new opportunities for therapeutic intervention for individuals suffering from this terrible disorder.