{"doi":"10.1073/pnas.2111643118","title":"Bach1 derepression is neuroprotective in a mouse model of Parkinson’s disease","abstract":"Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by the loss of nigrostriatal dopaminergic neurons. Mounting evidence suggests that Nrf2 is a promising target for neuroprotective interventions in PD. However, electrophilic chemical properties of the canonical Nrf2-based drugs cause irreversible alkylation of cysteine residues on cellular proteins resulting in side effects. Bach1 is a known transcriptional repressor of the Nrf2 pathway. We report that Bach1 levels are up-regulated in PD postmortem brains and preclinical models. Bach1 knockout (KO) mice were protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity and associated oxidative damage and neuroinflammation. Functional genomic analysis demonstrated that the neuroprotective effects in Bach1 KO mice was due to up-regulation of Bach1-targeted pathways that are associated with both Nrf2-dependent antioxidant response element (ARE) and Nrf2-independent non-ARE genes. Using a proprietary translational technology platform, a drug library screen identified a substituted benzimidazole as a Bach1 inhibitor that was validated as a nonelectrophile. Oral administration of the Bach1 inhibitor attenuated MPTP neurotoxicity in pre- and posttreatment paradigms. Bach1 inhibitor–induced neuroprotection was associated with the up-regulation of Bach1-targeted pathways in concurrence with the results from Bach1 KO mice. Our results suggest that genetic deletion as well as pharmacologic inhibition of Bach1 by a nonelectrophilic inhibitor is a promising therapeutic approach for PD.","journal":"Proceedings of the National Academy of Sciences","year":2021,"id":151595,"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":82,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9552,"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":644382,"name":"Navneet Ammal Kaidery","orcid":"0000-0002-3226-2107","position":1,"is_corresponding":false},{"id":645386,"name":"Otis C. Attucks","orcid":null,"position":2,"is_corresponding":false},{"id":645387,"name":"Erin McDade","orcid":null,"position":3,"is_corresponding":false},{"id":644383,"name":"Dmitry M. Hushpulian","orcid":"0000-0002-2171-9896","position":4,"is_corresponding":false},{"id":602622,"name":"Arsen Gaisin","orcid":null,"position":5,"is_corresponding":false},{"id":488719,"name":"Irina N. Gaisina","orcid":"0000-0002-8668-3222","position":6,"is_corresponding":false},{"id":534791,"name":"Young‐Hoon Ahn","orcid":"0000-0003-0765-3074","position":7,"is_corresponding":false},{"id":644384,"name":"С. В. Никулин","orcid":"0000-0002-7900-5810","position":8,"is_corresponding":false},{"id":644385,"name":"А. А. Полозников","orcid":"0000-0003-1816-8699","position":9,"is_corresponding":false},{"id":644386,"name":"Irina G. Gazaryan","orcid":"0000-0002-9670-5579","position":10,"is_corresponding":false},{"id":19758,"name":"Masayuki Yamamoto","orcid":"0000-0002-9073-9436","position":11,"is_corresponding":false},{"id":644387,"name":"Mitsuyo Matsumoto","orcid":"0000-0002-2918-9893","position":12,"is_corresponding":false},{"id":285807,"name":"Kazuhiko Igarashi","orcid":"0000-0002-2470-2475","position":13,"is_corresponding":false},{"id":564320,"name":"Sudarshana M. Sharma","orcid":"0000-0002-9745-0061","position":14,"is_corresponding":false},{"id":644388,"name":"Bobby Thomas","orcid":"0000-0001-9244-9726","position":15,"is_corresponding":false},{"id":644381,"name":"Manuj Ahuja","orcid":"0000-0002-4846-8249","position":0,"is_corresponding":true}],"reference_count":58,"raw_metadata":null,"created_at":"2026-07-18T23:43:16.823357Z","pmid":"34737234","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":[]}