Dataset Information

Proteomic profiling maps the molecular pathways underlying the neuroprotective effects of the kinase inhibitor BX795 in a patient-derived model of Parkinson's disease

ABSTRACT: Disease-modifying therapies remain an important unmet need for neurodegenerative diseases, including Parkinson’s disease (PD). The aim of this study was to investigate the molecular pathways affected by the multi-kinase inhibitor BX795, which is neuroprotective in an induced pluripotent stem cell (iPSC)-based model of familial PD. To this end, we performed proteomics analysis in iPSC-derived neurons from patients bearing the G209A (p.A53T) α-synuclein (αSyn) mutation vis-à-vis control neurons, in the absence or presence of BX795. Comparison between p.A53T versus control neurons in the absence of BX795, revealed differential expression of 640 proteins from which only 67 were down-regulated whilst the rest 573 were up-regulated. This large increase in protein expression was linked by GO enrichment analysis mainly to the biological processes of transcription, translation, protein synthesis and modification. Upon treatment with BX795, the levels of a cohort of 118 proteins, lying mostly within these biological processes and representing approximately 20% of the total dysregulated proteins in p.A53T neurons, were restored. Enrichment analysis using the DAVID and Reactome softwares showed that these proteins are predominantly associated with mRNA metabolism, mRNA transport and translation, protein metabolism and degradation processes. This outcome was specific to p.A53T-neurons as BX795 had no significant effect on the proteome of control neurons.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain, Stem Cell

DISEASE(S): Parkinson's Disease

SUBMITTER: Martina Samiotaki

LAB HEAD: Rebecca Matsas

PROVIDER: PXD019574 | Pride | 2023-03-10

REPOSITORIES: Pride

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

Antoniou Nasia N Prodromidou Kanella K Kouroupi Georgia G Boumpoureka Ioanna I Samiotaki Martina M Panayotou George G Xilouri Maria M Kloukina Ismini I Stefanis Leonidas L Grailhe Regis R Taoufik Era E Matsas Rebecca R

NPJ Parkinson's disease 20220211 1

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 ...[more]

PMID: 35149677

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