Mitochondrial dysfunction and alpha-synuclein aggregation and spread are central pathological processes in Parkinson's disease (PD), but the relationship between these processes is poorly understood, as are the mechanisms by which they lead to cell death. The central function of mitochondria is to produce energy, and considerable evidence suggests that mitochondrial dysfunction can promote alpha-synuclein misfolding, which could in turn lead to alpha-synuclein spread and neurodegeneration. In this proposal, we will test our central hypothesis that in PD, energy failure due to mitochondrial dysfunction promotes alpha-synuclein aggregation and spread in neurons, including in the brain. The overall objective of this proposal is to determine how energy failure regulates alpha-synuclein spread.

We will accomplish these objectives in two specific aims: (1) We will determine if energy failure promotes alpha-synuclein aggregation and spread in cultured neurons. Specifically, we will use chemical and genetic approaches to manipulate mitochondrial functions and determine the impact on alpha-synuclein aggregation and spread. We will also assess how alpha-synuclein misfolding impacts mitochondrial function and energy metabolism. (2) We will determine if mitochondrial dysfunction promotes alpha-synuclein spread in vulnerable dopamine neurons in the brain. To do this, we will generate mice with dopamine neurons that have dysfunctional mitochondria and determine if alpha-synuclein spread and neuronal degenerate is accelerated. We will also test whether providing an alternate fuel source protects against these changes and investigate how alpha-synuclein influences gene expression in the brain. Overall, these studies will yield new information about the causal relationships between energy failure and protein aggregation and spread in Parkinson's disease and reveal new therapeutic strategies to slow or stop alpha-synuclein spread and neuronal death.