Sexually Dimorphic miR-497 Regulates Alpha-Synuclein and Alpha-Synucleinopathy

Dementia with Lewy bodies (DLB) is a devastating neurological disease with no known cure. The pathologic substrate of DLB is cortical Lewy body pathology (LBP), which is present in 10-30% of individuals with dementia. LBP is made up of alpha-synuclein (alpha-SN) protein. We propose a research program to test the specific hypothesis that a sexually dimorphic microRNA (miRNA) referred to as miR-497 regulates alpha-SN in a manner that could contribute to DLB pathogenetically. In preliminary data, we found that miR-497 is differentially expressed in male versus female human cerebral cortex, and is also dysregulated in human brains with LBP independent of gender status. Further, miR-497 regulates alpha-SN expression in tissue cultured cells. We found previously that men have strongly (~three-fold) increased risk for developing autopsy-confirmed cortical LBP relative to women. We propose an integrated research plan including experiments designed to elucidate novel neurochemical mechanisms underlying DLB, with these Specific Aims: Specific Aim 1 „³ Test the hypothesis that sexually dimorphic miRNAs are dysregulated in LBP. Whether due to endogenous or environmental sex-linked factors, preliminary data indicate that miR-497 is sexually dimorphic and dysregulated in brains with LBP. Proposed studies will represent the state of the art in miRNA profiling using miRNA microarrays in human brain with respect to both gender differences and LBP Specific Aim 2 „³ Test the hypothesis that miR-497 regulates alpha-SN expression. Preliminary data indicate that miR-497 regulates alpha-SN. Primary cultured rat neurons will be transduced with lentiviral vectors expressing miR-497 (vs other control miRNAs) to test the hypothesis that miR-497 regulates alpha-SN. Following lentiviral transduction with miRNAs, we will demonstrate the full list of miR-497 targets in cultured primary neurons. These mechanistic studies will draw on the results of Aim #1 to evaluate environmental or hormonal factors that could influence the miRNA regulation of alpha-SN. These hypothesis-based experiments are necessary prerequisites to developing small RNA-based therapies that improve alpha-SN regulation in vivo.