Objective/Rationale:
The variations in FGF20 gene play important roles in developing Parkinson’s disease. Recently, we found such a genetic variation in FGF20 gene strongly associated with PD. That specific genetic variation causes more synthesized FGF20 protein in human brain and further induces alpha-synuclein over production-a well-known causative factor in familial form PD. This proposed study is designed to explore the inhibition of FGF20 and its biological function by microRNA.
Project Description:
We will design two versions of microRNA precursors; wild type and genetically modified. The modified microRNA will completely match that risk genetic variation in order to inhibit FGF20 synthesis in human cells. We can directly incubate human fibroblast cells with microRNAs to test their effects. For their long-term effects, we plan to deliver those modified miRNA by biological vehicles as an initial gene therapy in the cell model. We will use two different technologies to minitor FGF20 protein level in those cell models.
We also plan to test the correlation of FGF20 and the PD hall marker in human brain. The molecular mechanism by which FGF20 causes alpha-synulcein over production is included in this project too.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Due to the genetic variations, the effect of conventional medication varies considerably among PD patients. This study may help to develop a new treatment for PD patients carrying FGF20 gene risk variations. The delivery of genetically modified microRNA can be an effective way to decrease the risk to PD and as a potential new treatment to inhibit FGF20 synthesis, hence blocking its pathway leading to PD.
Anticipated Outcome:
To our knowledge, this study is the first of its kind to explore if microRNA can be used as a potential therapeutic tool. We expect that genetically modified miR-433 can reinstate its biological function to repress FGF20 synthesis and inhibit alpha-synuclein over production and aggregation, therefore lay the bases for the future gene therapy in animal model and patients.
Final Outcome
Dr. Wang found suggestive data that an individual’s FGF20 allele genotype influences levels of alpha-synuclein in postmortem brain tissue. However, limited numbers of brain samples made the finding difficult to confirm. Cell culture studies also indicated that FGF20 can increase expression of tyrosine hydroxylase and alpha-synuclein.