RNA Splicing Dysregulation in Parkinson’s Disease

Genetic mutations, altered RNA regulation, and protein aggregation are the main hallmarks of Parkinson’s disease (PD), a neurodegenerative disorder. Investigation into the molecular basis of the disease revealed that post-transcriptional regulation, specifically RNA processing, contributes to neuronal vulnerability in PD. Alterations in alternative splicing affecting genes involved in neuronal function and cellular homeostasis have been reported in PD, including SNCA, LRRK2, MAPT, PRKN, and BIN1. These alterations impact central neuronal pathways, including cytoskeletal maintenance, mitochondrial function, synaptic activity, oxidative stress, and intracellular trafficking. This review aims to provide an overview of alternative splicing in key PD gene transcripts, with a focus on their roles in pathogenesis and disease progression. Emerging data suggest that dysregulation of RNA binding proteins (RBPs) may influence RNA processing in PD. We will examine current evidence on the RNA regulatory networks in PD, highlighting the role of transcript isoforms and RBPs in neuronal dysfunction. Finally, we will discuss emerging experimental models such as 3D-brain organoids that offer new opportunities to investigate splicing regulation.