Jun 12, 2020

High Content Screening and Proteomic Analysis Identify the Kinase Inhibitor BX795 as a Potent Neuroprotective Compound in a Patient-Derived Model of Parkinson's Disease

BioRxiv : the Preprint Server for Biology
N. AntoniouRebecca Matsas

Abstract

Combining high throughput screening approaches with induced pluripotent stem cell (iPSC)-based disease models 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) lpha-synuclein 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 neuroprotective effects of BX795 that comprised 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-lpha-Synuclein in neuron-like 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 developed an adaptable platform based on p.A53T iPSC-derived neurons for drug screeni...Continue Reading

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Mentioned in this Paper

Body Regions
Patterns
Projections and Predictions
Neurons
Brain
Deformity
Structure of Cortex of Kidney
Axon
Neocortex
DNA Barcoding, Taxonomic

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