Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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

Sci Transl Med. 2020 Sep 9;12(560):eaau3960

Authors/Editors: Boussaad I
Obermaier CD
Hanss Z
Bobbili DR
Bolognin S
Glaab E
Wołyńska 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
Barrale M
Krainc D
Gasser T
Wissinger B
Krüger R
Publication Date: 2020
Type of Publication: Journal Article

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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