Identifying transcriptional changes contributing to the increased risk and degeneration in idiopathic Parkinson's disease

Abstract

Parkinson’s disease (PD) is a chronic disease characterized by the progressive degeneration of dopaminergic neurons and the deposition of lewy bodies, occurring in a stereotypical pattern across the brain, known as Braak staging. Idiopathic PD is proposed to result from a complex interaction of multiple risk genes interacting with the environment in concert with the aging process. Supporting this hypothesis are the multiple large scale GWAS that have identified 1,000s of SNPs, referring to 100’s of loci, that increase an individual’s risk of developing idiopathic PD. This thesis has provided the first evidence of a dysregulated idiopathic PD lncRNA (PARNA) expressed from a highly significant PD GWAS locus, which results in the down-regulation of multiple protein-coding target genes, the impairment of the mitochondrial OXPHOS pathway and the upregulation of α-Syn. These results suggest that PARNA contributes to idiopathic PD through the sensitivity to mitochondrial OXPHOS dysfunction and increased neurotoxic α-Syn expression. This thesis also showed that elevated expression of PARNA protects against both mitochondrial OXPHOS inhibition and α-Syn induced toxicity, providing the first evidence that a lncRNA may provide a novel therapeutic avenue to treat idiopathic PD. This thesis also used the novel approach of performing RNA-Seq in several tissues reflecting different degenerative states within an individual, a post-pathologically affected, pre-overt pathologically affected and a pathologically unaffected brain region, within our idiopathic PD cohort, allowed for the identification of differentially expressed genes and molecular pathways specifically contributing to the increased risk of developing idiopathic PD, as well as the early and late stages of idiopathic PD degeneration. These result lead to the identification of idiopathic PD novel genes that may provide early/predictive biomarkers and novel idiopathic PD molecular pathways which may lead to new therapeutics to prevent/delay the disease.