News

home News

[200925 Àú³Î¹ßÇ¥] A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease

À̵¿ÁØ ¦¢ 2020-09-24

HIT

46919

2020 Sep 9;12(560):eaau3960.
 doi: 10.1126/scitranslmed.aau3960.

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

Affiliations 

Abstract

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.




Prev [200925 Àú³Î¹ßÇ¥] Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degradin...
Next [201105]Àú³Î¹ßÇ¥ Microglial autophagy–associated phagocytosis is essential...