Study Rationale: Abnormal protein aggregation and prion-like aggregate spreading are hallmarks of the degenerative cascades of sporadic and familial Parkinson’s disease (PD). These toxic aggregates can damage cells, including neurons, and studies have implicated multiple mechanisms of aggregate toxicity in cellular PD pathology. Although no single cellular defect has emerged as a central intermediate in PD initiation or progression, PD risk alleles may have the potential to illuminate underlying biological mechanisms. We propose to examine whether a failure of cellular quality control mechanisms contributes to PD pathology.
Hypothesis: We hypothesize that PD phenotypes, at the molecular level, result from the failure of cellular quality control mechanisms and that finding ways to maintain (or augment) quality control capacity will provide access to new therapeutic strategies for PD and possibly other neurodegenerative disorders.
Study Design: Using powerful molecular visualization and discovery tools in disease-relevant cells, we will elucidate how individual types of protein aggregates linked with PD subtypes (including aggregates derived from people with PD) alter cellular pathways and affect cell survival and function. We will also use genetic and cell biological approaches to understand how quality control mechanisms collapse, either with aging or with PD-associated genetic variants. We will also test small molecule activators of lysosomal function for their ability to improve cellular health in the context of aging and PD mutations.
Impact on Diagnosis/Treatment of Parkinson’s disease: Our expectation is that this work will identify the critical cellular functions that are disrupted by protein aggregates and will help define how PD mutations alter the underlying mechanisms of dysfunctional protein homeostasis.
Next Steps for Development: If we can identify specific steps in protein quality control that are affected in PD, the next phase of experiments will involve a search for additional molecules that can bypass or repair such defects.