Two proteins, PINK1 and parkin, prevent cell death by breaking down damaged mitochondria, cell's energy generators. Mutations in the PINK1/PRKN genes - genetic changes that render these proteins unable to break down damaged mitochondria -- cause inherited Parkinson's disease (PD). We recently found that in the striatum -- a brain region involved in PD -- mitochondria in nerve endings are particularly vulnerable to mutations in the PINK1 gene. In the present study, we will create pre-clinical models of inherited Parkinson's by blocking the production of PINK1 and parkin. The models will help us clarify the role of these proteins in mitochondria in striatal nerve endings. We will also examine how the accumulation of damaged mitochondria in nerve endings contributes to Parkinson's disease.
In this study, we aim to determine whether the lack of PINK1 and parkin adequately models PD. We hypothesize that the lack of these proteins will cause the accumulation of damaged mitochondria in striatal nerve endings. This should eventually lead to neurodegeneration in the substantia nigra, the dopamine-producing brain region damaged in PD.
In this study, we will create pre-clinical models of inherited Parkinson's lacking PINK1 and parkin and use these models and several well-characterized experimental setups to determine whether mitochondria in striatal nerve endings are damaged. We will also determine whether mitochondrial damage and resulting energy crisis in striatal nerve endings precedes neurodegeneration in the substantia nigra. Then, using a novel experimental method, we will determine if mitochondria in the nerve endings that release dopamine from substantia nigra into striatum are especially susceptible to the damage.
Impact on Diagnosis/Treatment of Parkinson's disease:
This work will advance our understanding of neurodegeneration in inherited PINK1/PRKN-associated Parkinson's and, potentially, in PD with an unknown cause.
Next Steps for Development:
The experimental methods developed in the course of this study can be used to evaluate new therapies for PD.