The AKT modulator A-443654 reduces α-synuclein expression and normalizes ER stress and autophagy |
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Authors: | Mandi Gandelman Warunee Dansithong Stephen C Kales Sharan Paul Gentrie Maag Erika Aoyama Alexey Zakharov Ganesha Rai Thomas Dexheimer Brooke M Whitehill Hongmao Sun Ajit Jadhav Anton Simeonov Mark J Henderson Duong P Huynh Stefan M Pulst Daniel R Scoles |
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Institution: | 1.Department of Neurology, University of Utah, Salt Lake City, Utah, USA;2.Department of Neurology, National Center for Advancing Translational Sciences (NCATS), Rockville, Maryland, USA;3.Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan, USA |
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Abstract: | Accumulation of α-synuclein is a main underlying pathological feature of Parkinson’s disease and α-synucleinopathies, for which lowering expression of the α-synuclein gene (SNCA) is a potential therapeutic avenue. Using a cell-based luciferase reporter of SNCA expression we performed a quantitative high-throughput screen of 155,885 compounds and identified A-443654, an inhibitor of the multiple functional kinase AKT, as a potent inhibitor of SNCA. HEK-293 cells with CAG repeat expanded ATXN2 (ATXN2-Q58 cells) have increased levels of α-synuclein. We found that A-443654 normalized levels of both SNCA mRNA and α-synuclein monomers and oligomers in ATXN2-Q58 cells. A-443654 also normalized levels of α-synuclein in fibroblasts and iPSC-derived dopaminergic neurons from a patient carrying a triplication of the SNCA gene. Analysis of autophagy and endoplasmic reticulum stress markers showed that A-443654 successfully prevented α-synuclein toxicity and restored cell function in ATXN2-Q58 cells, normalizing the levels of mTOR, LC3-II, p62, STAU1, BiP, and CHOP. A-443654 also decreased the expression of DCLK1, an inhibitor of α-synuclein lysosomal degradation. Our study identifies A-443654 and AKT inhibition as a potential strategy for reducing SNCA expression and treating Parkinson’s disease pathology. |
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Keywords: | Parkinson disease alpha-synuclein (α -synuclein) SNCA AKT A-443654 high-throughput screening (HTS) endoplasmic reticulum stress (ER stress) STAU1 staufen1 autophagy |
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