Sruthi Vijayaraghavan

Role of Aberrant mRNA Splicing in Parkinson's Disease Progression and Potential Gene Therapies

Started May 20, 2024

Abstract or project description

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopamine-producing neurons in the brain. PD is the second-most common neurodegenerative disorder in the United States, with about 500,000 Americans diagnosed and experts estimating 500,000 more Americans undiagnosed (NINDS, 2023). Alternative splicing, a critical post-transcriptional process, generates protein diversity by producing multiple mRNA isoforms from a single gene. In the brain, this process supports complex neuronal functions but also increases the chance of aberrant splicing, which contributes to neurodegenerative diseases such as Parkinson's disease. Key PD-related genes including PARK2, LRRK2, SNCA, and PINK1, exhibit splicing errors that impair protein degradation, mitochondrial maintenance, and synaptic function, leading to neuronal damage. Aberrant splicing in these genes disrupts normal cellular processes, causing protein misfolding and aggregation that contribute to PD progression. Recent research has highlighted therapeutic approaches targeting these splicing defects, including RNA interference (RNAi) and CRISPR-Cas9 gene editing. RNAi offers potential for reducing toxic protein accumulation by silencing specific gene expression, while CRISPR-Cas9 presents possibilities for correcting genetic mutations directly. Both technologies show promise in mitigating PD symptoms, but challenges remain, for example in delivering therapies across the blood-brain barrier and ethical considerations. Understanding the role of alternative splicing in PD pathogenesis is crucial for developing effective treatment strategies that address the underlying cause rather than just masking symptoms as current treatments do.