Objective/Rationale:
Mutations in the LRRK2 gene occur with high frequency in familial and sporadic Parkinson disease. We have established a R1441G-LRRK2 transgenic pre-clinical model that recapitulates several cardinal Parkinson disease symptoms including axonal degeneration of dopaminergic neurons and deficits in dopamine release. Our goal is to dissect the molecular and cellular pathways that underlie this synaptic dysfunction and axonal degeneration.
Project Description:
In Parkinson’s disease, dopaminergic synaptic dysfunction and axonal degeneration are believed to be an upstream event, and these exact symptoms have been observed in our R1441G-LRRK2 transgenic mice. Therefore, we intend to investigate the mechanism underlying these two deficits by: A). using cutting edge electrophysiological and neurochemical assays to conduct an in-depth examination of dopaminergic neurotransmission, release and storage. B). determining the onset of axonal degeneration in dopaminergic neurons by examining axonal pathology in different age groups of transgenic mice. C) examining whether the same kinase pathway found to affect actin dynamics in other neurological diseases also contributes to the axonal degeneration seen in our animals.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Identification of the pathways that lead to synaptic transmission deficits and axonal degeneration in our R1441G-LRRK2 transgenic mice will generate a number of therapeutic intervention targets for Parkinson’s disease. In addition, identifying a synaptic transmission deficit will serve as a platform for screening drugs and molecules that can ameliorate this deficit.
Anticipated Outcome:
We have already detected an overall dopamine release deficit in our animals. In this project, we will conduct an in-depth analysis of this deficit by using two novel and sophisticated electrophysiological and neurochemical assays. By characterizing the axonal pathology in different age groups of R1441G-LRRK2 transgenic mice, we will determine the on-set of neurodegeneration. Finally, we will be able to determine whether actin dynamics are involved in dopaminergic axonal degeneration in R1441G-LRRK2 transgenic mice.