Combining high throughput screening with induced pluripotent stem cell (iPSC)-based disease modeling is a promising unbiased strategy to identify therapies for neurodegenerative disorders. Here we applied high content imaging on iPSC-derived neurons from patients with familial Parkinson’s disease bearing the G209A (p.A53T) α-synuclein (αSyn) mutation and launched a screening campaign on a small kinase inhibitor library. We thus identified the multi-kinase inhibitor BX795 that at a single dose effectively restores disease-associated neurodegenerative phenotypes. Proteomics profiling mapped the molecular pathways underlying the protective effects of BX795, comprising a cohort of 118 protein-mediators of the core biological processes of RNA metabolism, protein synthesis, modification and clearance, and stress response, all linked to the mTORC1 signaling hub. Taken together, we have identified a promising small molecule with neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.
Nasia Antoniou, Kanella Prodromidou, Georgia Kouroupi, Ioanna Boumpoureka, Martina Samiotaki, George Panayotou, Maria Xilouri, Ismini Kloukina, Leonidas Stefanis Regis Grailhe, Era Taoufik, Rebecca Matsas
High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s disease
NPJ Parkinsons Dis. 2022 Feb 11;8(1):15. http://doi.org/10.1038/s41531-022-00278-y