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

  • Transversal Translational Medicine
September 09, 2020 By:
  • Boussaad I
  • Obermaier CD
  • Hanss Z
  • Bobbili DR
  • Bolognin S
  • Glaab E
  • Wolynska K
  • Weisschuh N
  • De Conti L
  • May C
  • Giesert F
  • Grossmann D
  • Lambert A
  • Kirchen S
  • Biryukov M
  • Burbulla LF
  • Massart F
  • Bohler J
  • Cruciani G
  • Schmid B
  • Kurz-Drexler A
  • May P
  • Duga S
  • Klein C
  • Schwamborn JC
  • Marcus K
  • Woitalla D
  • Vogt Weisenhorn DM
  • Wurst W
  • Baralle M
  • Krainc D
  • Gasser T
  • Wissinger B
  • Kruger R.

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.

2020 Sep. Sci Transl Med.12(560).
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