Objective/Rationale:
Alpha synuclein is a protein that in excessive amounts is implicated in Parkinson’s disease (PD). Alpha synuclein is also known to be the major constituent of a signature patholological feature of PD called a Lewy body, This grant plans to reduce the levels of experimental Parkinson’s disease using a gene therapy approach to deliver microRNAs in which the synthesis of alpha synuclein is inhibited. Two specific microRNAs will be tested for both behavioral and anatomical neuroprotection.
Project Description:
Pre-clinical models will be treated with a neurotoxin called MPTP. This neurotoxin causes dopamine cell death in part by accumulating alpha-synuclein. Prior to the MPTP lesion, they will receive an injection into the substantia nigra of a lentivirus encoding for microRNAs 7 and 153. These two microRNAs have been shown to reduce alpha-synuclein levels in culture. We will use a battery of tests including the stepping test and cylinder test to assess whether the lenti-microRNAs can functionally reduce motor disabilities induced by this toxin. Then the pre-clinical models will be sacrificed and the abilities of these microRNA’s to reduce the MPTP-induced degenerative process in the nigrostriatal system will be assessed.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
It is now appreciated that alpha synuclein over expression and misfolding is a major pathological feature in Parkinson’s disease. Methods that reduce alpha synuclein expression could lead to a major treatment paradigm shift in the treatment of Parkinson’s disease. This grant will test the hypothesis that gene delivery of microRNAs to the non-coding region of protein RNA synthesis can reduce the structural and functional expression of alpha-synuclein in the nigrostriatal system. If successful, this can be applied to other regions in which alpha synuclein accumulates.
Anticipated Outcome:
We expect to learn the following:
- Can we successfully deliver microRNA’s using gene therapy
- Can gene delivery of microRNA’s 7 and 153 reduce motor disability in MPTP-treated pre-clinical models
- Can gene delivery of microRNA’s 7 and 153 protect the nigrostriatal system from MPTP toxicity.