4.8 Article

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

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SCIENCE TRANSLATIONAL MEDICINE
卷 12, 期 560, 页码 -

出版社

AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aau3960

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资金

  1. Luxembourg National Research Fund (FNR) within the PEARL programme (FNR) [FNR/P13/6682797]
  2. German Research Council (DFG) [KR2119/8-1, KL1134/11-1]
  3. EU Joint Program-Neurodegenerative Diseases (JPND)
  4. European Union's Horizon2020 research and innovation program [692320]
  5. NIH [R01NS076054, R37 NS096241]
  6. Luxembourg National Research Fund (FNR) [C13/BM/5782168]
  7. HUPO Brain Proteome Project, PURE (a project of Nordrhein-Westfalen, a federal German state)
  8. Deutsche Parkinson Gesellschaft e.V.
  9. Verein zur Durchfuhrung Neurowissenschaftlicher Tagungen e.V. (Berlin, Germany)
  10. German Science Foundation Collaborative Research Centre (CRC) [CRC 870, WU 164/5-1]
  11. Munich Cluster for Systems Neurology [EXC 1010]
  12. Bavarian Ministry of Education, Culture and Science [Human Induced Pluripotent Stem Cells (ForIPS)]
  13. Helmholtz Portfolio Theme Supercomputing and Modelling for the Human Brain (SMHB)
  14. German Federal Ministry of Education and Research (BMBF) [031A430E]
  15. Hermann and Lilly Schilling Foundation
  16. EU Joint Program-Neurodegenerative Diseases (COURAGE-PD)
  17. EU Joint Program-Neurodegenerative Diseases (3DPD)

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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, mitochondria! 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 mitochondria! 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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