Exploring RNA Splicing as a Potential New Drug Avenue for Parkinson’s Disease

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease. Approximately 60,000 people get diagnosed with PD in the United States alone and around 10 million people live with this motor disorder.

By T. Chakraborty, Ph.D. 

With the aging population of the world increasing, this age-dependent neurodegenerative disease is a substantial socioeconomic burden. Further complicating the situation is the lack of disease-modifying therapy, while the treatments available can only take care of the symptoms [1]. 

Etiology of Parkinson’s disease

The key pathophysiological hallmark of Parkinson’s disease is the loss of dopaminergic neurons in the substantia nigra region of the brain. The underlying factors leading to this neuronal loss is not clearly understood. Mendelian genetics accounts for around 10 % of PD cases. The genes involved in genetic PD are termed as PARK genes. The remaining 90% of PD cases are idiopathic. Multiple genome-wide associated studies have identified genetic and environmental risk factors that may contribute to disease etiology. Thus, owing to the disease’s diverse nature, the search for disease-modifying therapy has been challenging. A recent study titled “A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease” published in a Science group journal shed some light on a potential new mechanism that may help in drug development [2]. 

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RNA mis-splicing as a potential mechanism of neurodegeneration

The study by Boussaad et al. demonstrated that a mutation in one of the disease-causing gene, DJ-1 leads to mis-splicing of DJ-1. The study used fibroblast cells as well as induced pluripotent stem cell derived neurons from patients with the mutation in this gene to show that splicing error leads to skipping of an exon, which leads to reduced full-length protein production. To confirm the findings, the authors further altered U1 snRNA, which restored DJ-1 protein production. Since DJ-1 mutation is rare and only observed in a minor number of PD cases, the authors further performed burden analysis on two publicly available databases, namely PPMI and PDGSC. This analysis revealed that PD patients mostly have problems splicing, showing that this novel mechanism of cellular death may be used as a drug target. 

The first author in the paper Dr. Boussaad, a researcher at the Luxembourg Centre for Systems Biomedicine (LCSB), claimed “This insight fundamentally changes our view of the causes of the disease and presents entirely new possibilities for treatment.”

Dr. Rejko Krüger, MD, from the University of Luxembourg, the corresponding author for the study, said, “In the patients, an essential tool for the assembly of the protein DJ-1 fails to dock properly. In scientific terms, we call that exon skipping. As a result of this defect, the protein doesn’t get built at all.” He concluded, “Only by combining numerous disciplines — from medical practice, to laboratory research, to computer science — could we understand the cause and at the same time identify active substances for potential treatment.” [2,3]


Though this study demonstrated a novel mechanism of cell death in Parkinson’s disease, it is to be noted that the mutation showed in the study is extremely rare and does not account for more than 90% of the cases. Additionally, all the studies were performed in cultured cells, which are different than in vivo studies. Further investigation into common mutants or GWAS candidate genes will be beneficial and help understand the mechanism of neuronal loss. 

Related Article: Spotlight: New Gene Therapies on the Horizon for the Treatment of Neurogenetic Diseases


1. https://www.parkinson.org/Understanding-Parkinsons/Statistics

2. https://stm.sciencemag.org/content/12/560/eaau3960

3. https://parkinsonsnewstoday.com/2020/09/15/research-reveals-how-park7-gene-mutations-affecting-dj-1-protein-cause-early-onset-parkinsons/?preview_id=37676

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