Funded Studies
Objective/Rationale:
Mutations in the gene for the protein parkin gene can cause Parkinson’s disease (PD), and parkin is involved in the breakdown of damaged proteins. This makes parkin an important focus of study, especially of how it may influence alpha-synuclein, another protein key to Parkinson’s. This project will study how parkin expression alters the handling of alpha-synuclein in the dopamine neurons that are most vulnerable and lost in people with PD.
Project Description:
We will utilize viral vectors (a tool to deliver genetic material into cells) as carriers for the parkin and alpha-synuclein genes and inject them directly into the area of the brain of pre-clinical models where dopamine neurons are found in high density. After two months, brain tissue will be processed to determine the concentration of alpha-synuclein in the presence and absence of parkin function. We will also examine how found in this compartment is modified by a process called phosphorylation.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Evidence suggesting that increased function of parkin could mitigate toxic effects of alpha-synuclein would support the development of drugs targeting this pathway.
Anticipated Outcome:
We will learn how two mutations of parkin might lead to Parkinson’s disease and thus be able to develop treatments to precisely target that mechanism. For example, modifications of proteins (like alpha-synuclein) tell us something about how they are processed in the cells and help us draw links between early abnormalities in cells and later events that lead to cell death.
Final Outcome
The benefits of parkin, the protein linked to a rare inherited form of Parkinson's disease (PD), remain unclear. The lack of functional parkin is associated with PD, suggesting that this protein could protect brain cells from damage. Therefore, the addition of parkin to the brain cells damaged in the course of PD could be therapeutic. In this study, we tested this hypothesis in a pre-clinical model with Parkinson's features by adding either normal parkin or its abnormal, non-functioning version to the cells damaged by alpha-synuclein, a protein that clumps in the brains of people with PD. The models we used in this study lacked their own parkin, which allowed us to ensure that their parkin does not skew the results of the study. We found that parkin does not have a robust protective effect; however, we observed several interesting differences between models with normal parkin and those without their own parkin. This result would aid in further research efforts to elucidate the effects of parkin on alpha-synuclein-induced damage of brain cells.
May 2016
Presentations & Publications
The results have not been published so far but are under preparation at the time of this submission.