{"doi":"10.1016/j.jbc.2021.101191","title":"The AKT modulator A-443654 reduces α-synuclein expression and normalizes ER stress and autophagy","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.","journal":"Journal of Biological Chemistry","year":2021,"id":159700,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":40,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9519,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":312904,"name":"Warunee Dansithong","orcid":null,"position":1,"is_corresponding":false},{"id":550316,"name":"Stephen C. Kales","orcid":"0000-0002-8702-5766","position":2,"is_corresponding":false},{"id":485377,"name":"Sharan Paul","orcid":"0000-0002-9845-3125","position":3,"is_corresponding":false},{"id":671703,"name":"Gentrie Maag","orcid":null,"position":4,"is_corresponding":false},{"id":671704,"name":"Erika Aoyama","orcid":null,"position":5,"is_corresponding":false},{"id":12541,"name":"Alexey Zakharov","orcid":"0000-0003-2466-1711","position":6,"is_corresponding":false},{"id":268294,"name":"Ganesha Rai","orcid":"0000-0001-9763-9641","position":7,"is_corresponding":false},{"id":671060,"name":"Thomas S. Dexheimer","orcid":"0000-0002-6444-3121","position":8,"is_corresponding":false},{"id":671705,"name":"Brooke M. Whitehill","orcid":null,"position":9,"is_corresponding":false},{"id":332246,"name":"Hongmao Sun","orcid":"0000-0003-4042-6498","position":10,"is_corresponding":false},{"id":262007,"name":"Ajit Jadhav","orcid":"0000-0001-7955-1451","position":11,"is_corresponding":false},{"id":228423,"name":"Anton Simeonov","orcid":"0000-0002-4523-9977","position":12,"is_corresponding":false},{"id":287614,"name":"Mark J. Henderson","orcid":"0000-0001-8590-7338","position":13,"is_corresponding":false},{"id":671706,"name":"Duong P. Huynh","orcid":null,"position":14,"is_corresponding":false},{"id":291788,"name":"Stefan M. Pulst","orcid":"0000-0003-0883-7879","position":15,"is_corresponding":false},{"id":485376,"name":"Daniel R. Scoles","orcid":"0000-0002-3271-9912","position":16,"is_corresponding":false},{"id":485378,"name":"Mandi Gandelman","orcid":"0000-0003-2697-0390","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-18T23:44:39.550981Z","pmid":"34520759","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}