Τίτλος:
High content screening and proteomic analysis identify a kinase inhibitor that rescues pathological phenotypes in a patient-derived model of Parkinson’s disease
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
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. © 2022, The Author(s).
Συγγραφείς:
Antoniou, N.
Prodromidou, K.
Kouroupi, G.
Boumpoureka, I.
Samiotaki, M.
Panayotou, G.
Xilouri, M.
Kloukina, I.
Stefanis, L.
Grailhe, R.
Taoufik, E.
Matsas, R.
Περιοδικό:
npj Parkinson's Disease
Εκδότης:
Institute of Geographic Sciences and Natural Resources Research
Λέξεις-κλειδιά:
alpha synuclein; brain derived neurotrophic factor; cyclic AMP dependent protein kinase; glial cell line derived neurotrophic factor; green fluorescent protein; heat shock transcription factor 1; initiation factor 2alpha; mammalian target of rapamycin; mammalian target of rapamycin complex 1; phosphoinositide dependent protein kinase 1; phosphotransferase inhibitor; sequestosome 1, animal cell; animal experiment; animal model; antibody labeling; Article; bioinformatics; cell survival; cell viability; confocal microscopy; controlled study; degenerative disease; embryoid body; endoplasmic reticulum stress; enzyme linked immunosorbent assay; fluorescence microscopy; gene expression; gene mutation; gene ontology; gene overexpression; genetic transfection; high content screening; high performance liquid chromatography; high throughput screening; image analysis; immunoblotting; immunocytochemistry; liquid chromatography-mass spectrometry; mass spectrometry; mitochondrial biogenesis; nerve cell differentiation; nerve degeneration; neural stem cell; neurite outgrowth; neuroprotection; oxidative stress; Parkinson disease; particle size; pathology; phenotype; physiological stress; pluripotent stem cell; protein aggregation; protein expression; protein fingerprinting; protein phosphorylation; protein synthesis; proteomics; RNA isolation; RNA metabolism; RNA splicing; signal transduction; unfolded protein response; upregulation; virus infection
DOI:
10.1038/s41531-022-00278-y
