Objective/Rationale:
Our laboratory has recently shown that a genetic variant of the gene UCH-L1, associated with reduced risk for Parkinson’s disease, specifically prevents the generation of damaging free radicals and cell death following oxidative stress in neuronal cells in culture; we plan to extend these results to an in vivo pre-clinical model, in which we will examine whether expression of this polymorphic variant protects against dopaminergic neuron death induced by the neurotoxin MPTP.
Project Description:
In order to effectively deliver the variant S18Y or the normal, wild type UCH-L1 protein to mouse dopaminergic neurons, we will first generate adenoviruses that express these genes. We will then use a pump to deliver these viruses specifically within mouse substantia nigra. Following verification of UCH-L1 protein expression, we will inject mice with the neurotoxin MPTP, which induces selective death of nigral dopaminergic neurons. We will then assay the different groups of mice, one expressing the normal UCH-L1 protein and the other the S18Y variant, for degeneration of dopaminergic neurons and for amount of dopamine. If the results from cell culture experiments reflect what is happening in vivo, we expect that the group expressing the S18Y variant will be protected from MPTP toxicity.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
If the S18Y variant of UCH-L1 protects from MPTP toxicity, this will mean that individuals that express this variant have an endogenous mechanism of protection against oxidative stress. Although we do not know what causes Parkinson’s disease, a major theory is that oxidative stress plays a role. These results would help explain the protective effect of carrying this particular genetic variant, and could pave the way for novel therapies that aim to boost endogenous antioxidant defense mechanisms.
Anticipated Outcome:
If S18Y UCH-L1 expression protects dopaminergic neurons from MPTP toxicity, this will prove that within the complex environment of a mammalian organism the expression of this single genetic variant, which exists in about 20% of the human population, can affect favorably the response to environmental toxins that may trigger Parkinson’s disease in humans. If so, more research will be warranted into the mechanisms through which this genetic variant induces this effect, and gene therapy or pharmacological means may be utilized as strategies to stimulate this novel protective pathway as a treatment for Parkinson’s disease.