High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson's disease

Nasia Antoniou, Kanella Prodromidou, Georgia Kouroupi, Ioanna Boumpoureka, Martina Samiotaki, George Panayotou, Maria Xilouri, Ismini Kloukina, Leonidas Stefanis, Regis Grailhe, Era Taoufik, Rebecca Matsas

Research output: Contribution to journalArticleResearchpeer-review

11 Citations (Scopus)

Abstract

Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease modeling represents 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. In agreement, expression of human p.A53T-αSyn in neuronal cells affected key components of the mTORC1 pathway resulting in aberrant protein synthesis that was restored in the presence of BX795 with concurrent facilitation of autophagy. Taken together, we have identified a promising small molecule with neuroprotective actions as candidate therapeutic for PD and other protein conformational disorders.

Original languageEnglish
Article number15
Journalnpj Parkinson's Disease
Volume8
Issue number1
DOIs
Publication statusPublished - 11 Feb 2022
Externally publishedYes

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