We have recently identified Parkin-Interacting Substrate (PARIS), a Kruppel associated box (KRAB) and zinc finger protein, as a substrate of the parkin, E3 ubiquitin ligase. PARIS accumulates in pre-clinical models of Parkin inactivation and specifically kills dopamine neurons. Parkin is also inactivated and PARIS accumulates in the substantia nigra in PD. Thus, PARIS may play a role in sporadic PD.
Here, we hypothesize that alpha-synuclein-induced oxidative stress causes parkin inactivation that results in accumulation of PARIS and that PARIS mediates alpha-synuclein neurodegeneration in sporadic PD.
To determine if PARIS mediates alpha-synuclein-induced dopamine neuron degeneration, we will test whether the absence of PARIS reduces the loss of dopamine neurons and the accompanying behavior deficits in two different pre-clinical models of alpha-synuclein-induced dopamine neuron degeneration.
Impact on Diagnosis/Treatment of Parkinson's disease:
We expect that the experimental results from the proposed plan will establish PARIS as a major player in alpha-synuclein-induced neurodegeneration.
Since PARIS is a transcriptional repressor (proteins that bind to specific sites on DNA), it is important to identify specific targets of PARIS in alpha-synuclein-induced neurodegeneration which might enable us to discover novel molecules and/or pathways modulating neurodegeneration in PD and alpha-synucleinopathies in the future.
Next Steps for Development:
We will screen and identify pharmacological inhibitors of PARIS for therapeutic intervention.