Objective/Rationale:
Brain cells rely on very efficient surveillance systems to identify defective components and break them apart to avoid accumulation and toxicity. Research has shown that in the brain cells of people with Parkinson’s disease (PD), one of these cleaning mechanisms [chaperone-mediated autophagy or CMA] malfunctions, contributing to cellular cluttering and toxicity. In this study investigators intend to identify the contribution of LRRK2, a protein often altered in PD, to the failure of this cleaning process.
Project Description:
These researchers have developed systems that permit them to reconstitute each of the steps that take place in brain cells to assure proper quality control, from the identification of the defective component to their delivery and destruction in the cellular cleaning systems. Using these methods, they intend to add normal LRRK2 protein or the different mutant proteins identified in PD patients and directly analyze the steps that are altered by the abnormal LRRK2. The strength of the collaboration between these two groups is that they can combine findings of models reconstituted outside cells with findings in intact brain cells obtained from different pre-clinical models of PD. This back and forth between both systems has proven very efficient in accelerating the pace of discovery in previous collaborative efforts.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
This is an ideal moment to conduct this research because of rapid advances in the last five years in understanding of cell surveillance mechanisms, which is now driving the development of drugs that can enhance the activity of the cellular cleaning systems. Once researchers identify the step or steps of the cleaning process altered by LRRK2 in PD brains, they should be able to utilize drugs to restore normal function and prevent cellular toxicity.
Anticipated Outcome:
Through these studies researchers expect to understand how LRRK2 mutations in PD disrupt the normal quality control mechanisms in brain cells, which should help identify means to prevent the toxic effect of LRRK2 and restore normal cellular cleaning.