Alternative pre-mRNA Splicing and Gene Expression Patterns in Midbrain Lineage Cells Carrying Familial Parkinson’s Disease Mutations
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Parkinson’s disease (PD) arises from genetic and environmental factors. Human genetics has identified mutations in ∼20 inherited familial genes linked to monogenic forms of PD. To investigate the effects of individual familial PD mutations, human pluripotent embryonic stem cells (hPSCs) carrying 12 distinct familial PD mutations were differentiated into midbrain lineage cells, including dopaminergic (mDA) neurons. Global gene expression and pre-mRNA splicing patterns were analyzed in midbrain cultures carrying pathogenic PD mutations in the PRKN , SNCA , LRRK2 , PINK1 , DNAJC6 , FBXO7 , SYNJ1 , DJ1, VPS13C , ATP13A2 and GBA1 genes. We have grouped the analysis of these familial PD mutations to genes expressed in mDA neurons and whose pre-mRNA splicing changes are linked to known PD defects in transport, cytoskeleton, lysosomes and mitochondria. Importantly, we have also shown that subsets of these splicing changes overlap with changes found in PD patient postmortem brains. Mutation-specific pre-mRNA isoforms may function as both diagnostic biomarkers for familial PD-associated genotypes and promising therapeutic targets.
