Study Rationale:
Abnormal protein aggregation and prion-like aggregate spreading are hallmarks of the degenerative cascades of sporadic and familial Parkinson’s disease (PD) and can damage cells, including neurons. Multiple mechanisms of aggregate toxicity have been implicated in cellular PD pathology, and PD risk alleles may have the potential to illuminate additional underlying biological mechanisms.
Hypothesis:
Parkinson’s disease, at the molecular level, results from the failure of cellular quality control (QC) mechanisms, and finding ways to maintain (or augment) QC capacity will provide 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 strains (including patient-derived aggregates) alter cellular pathways, including effects on cell survival and function. We will also use genetic approaches to understand what cellular proteins promote processing of PD-related aggregates.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Our expectation is that this work will identify those critical cellular functions that are disrupted by protein aggregates and will help define how mutations alter the underlying mechanisms of dysfunctional proteostasis.
Next Steps for Development:
If specific steps in protein quality control affected in PD can be identified, the next phase of experiments will involve a search for molecules that can bypass or repair such defects.