![]() Mencke, Pauline ![]() ![]() in Frontiers in Neurology (2020) Detailed reference viewed: 21 (0 UL)![]() Boussaad, Ibrahim ![]() in Science translational medicine (2020), 12(560), 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 ... [more ▼] 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. [less ▲] Detailed reference viewed: 123 (6 UL)![]() Hanss, Zoé ![]() ![]() ![]() in Frontiers in Genetics (2019) Detailed reference viewed: 93 (19 UL)![]() Monzel, Anna Sophia ![]() ![]() ![]() in Stem Cell Reports (2017) Detailed reference viewed: 571 (49 UL) |
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