Our data show that the enzyme USP13 is dramatically increased (two-fold) in sporadic Parkinson’s brains, and cell culture studies suggest that USP13 de-ubiquitinates (modifies) the parkin,protein, indicating that USP13 may regulate parkin stability.
We hypothesize that USP13 regulates Parkin stability and modulates alpha-synuclein clearance and is a potential therapeutic target for neurodegeneration.
This project aims to study the role of USP13 in parkin stability and downstream effects on misfolded protein clearance and dopaminergic neuron protection. We will determine the effects of USP13 manipulation (over-expression or deletion) on parkin and dopaminergic neurons in wild type (typical) and parkin-deficient models and in vitro using midbrain neurons. We will also use USP13 gene transfer into alpha-synuclein overexpressing model to determine whether USP13 modulates parkin-mediated alpha-synuclein clearance via autophagy (intracellular degradation system), or whether USP13 directly modifies alpha-synuclein metabolism.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
The relationship between USP13 and parkin is a novel area of investigation that may identify therapeutic drug targets in neurodegeneration.