Research ArticleParkinson’s Disease

A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson’s disease

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Science Translational Medicine  09 Sep 2020:
Vol. 12, Issue 560, eaau3960
DOI: 10.1126/scitranslmed.aau3960

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PARK(7) preservation

Mutations in PARK7 lead to the development of early-onset Parkinson’s disease (PD), a neurodegenerative condition for which there are currently no effective treatments. Here, Boussaad et al. identified an exonic splicing mutation in PARK7 linked to PD and studied the effect of this mutation in patient-derived cellular models. The mutation resulted in impaired splicing, reduced production of DJ-1 protein, and consequent mitochondrial dysfunction. Rescuing the aberrant splicing with the kinetin analog RECTAS in combination with phenylbutyric acid rescued neuronal loss in patient-derived brain organoids. The results suggest that precision medicine targeting specific molecular signatures could be an effective strategy for PD and possibly other neurodegenerative diseases.


Parkinson’s disease (PD) is a heterogeneous neurodegenerative disorder with monogenic forms representing prototypes of the underlying molecular pathology and reproducing to variable degrees the sporadic forms of the disease. Using a patient-based in vitro model of PARK7-linked PD, we identified a U1-dependent splicing defect causing a drastic reduction in DJ-1 protein and, consequently, mitochondrial dysfunction. Targeting defective exon skipping with genetically engineered U1-snRNA recovered DJ-1 protein expression in neuronal precursor cells and differentiated neurons. After prioritization of candidate drugs, we identified and validated a combinatorial treatment with the small-molecule compounds rectifier of aberrant splicing (RECTAS) and phenylbutyric acid, which restored DJ-1 protein and mitochondrial dysfunction in patient-derived fibroblasts as well as dopaminergic neuronal cell loss in mutant midbrain organoids. Our analysis of a large number of exomes revealed that U1 splice-site mutations were enriched in sporadic PD patients. Therefore, our study suggests an alternative strategy to restore cellular abnormalities in in vitro models of PD and provides a proof of concept for neuroprotection based on precision medicine strategies in PD.

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