{"doi":"10.1073/pnas.2210712120","title":"Integrated regulation of dopaminergic and epigenetic effectors of neuroprotection in Parkinson’s disease models","abstract":"Whole-exome sequencing of Parkinson’s disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in the tyrosine nonreceptor kinase-2 ( TNK2 ) gene. Although this kinase had a previously demonstrated activity in preventing the endocytosis of the dopamine reuptake transporter (DAT), a causal role for TNK2-associated dysfunction in PD remains unresolved. We postulated the dopaminergic neurodegeneration resulting from patient-associated variants in TNK2 were a consequence of aberrant or prolonged TNK2 overactivity, the latter being a failure in TNK2 degradation by an E3 ubiquitin ligase, neuronal precursor cell-expressed developmentally down-regulated-4 (NEDD4). Interestingly, systemic RNA interference protein-3 (SID-3) is the sole TNK2 ortholog in the nematode Caenorhabditis elegans , where it is an established effector of epigenetic gene silencing mediated through the dsRNA-transporter, SID-1. We hypothesized that TNK2/SID-3 represents a node of integrated dopaminergic and epigenetic signaling essential to neuronal homeostasis. Use of a TNK2 inhibitor (AIM-100) or a NEDD4 activator [N-aryl benzimidazole 2 (NAB2)] in bioassays for either dopamine- or dsRNA-uptake into worm dopaminergic neurons revealed that sid-3 mutants displayed robust neuroprotection from 6-hydroxydopamine (6-OHDA) exposures, as did AIM-100 or NAB2-treated wild-type animals. Furthermore, NEDD4 activation by NAB2 in rat primary neurons correlated to a reduction in TNK2 levels and the attenuation of 6-OHDA neurotoxicity. CRISPR-edited nematodes engineered to endogenously express SID-3 variants analogous to TNK2 PD-associated SNPs exhibited enhanced susceptibility to dopaminergic neurodegeneration and circumvented the RNAi resistance characteristic of SID-3 dysfunction. This research exemplifies a molecular etiology for PD whereby dopaminergic and epigenetic signaling are coordinately regulated to confer susceptibility or resilience to neurodegeneration.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":345632,"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":12,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":911045,"name":"Shannon N. Russell","orcid":"0000-0003-4543-8391","position":1,"is_corresponding":false},{"id":1085596,"name":"Nathan A. Moniz","orcid":"0000-0002-8706-0131","position":2,"is_corresponding":false},{"id":911044,"name":"Kylie Peter","orcid":"0000-0002-5571-7346","position":3,"is_corresponding":false},{"id":1085597,"name":"Lena M. Seyfarth","orcid":"0000-0002-0965-2844","position":4,"is_corresponding":false},{"id":1064867,"name":"Madison Scott","orcid":"0000-0003-4377-4893","position":5,"is_corresponding":false},{"id":271576,"name":"Hana Park","orcid":"0000-0001-5563-5255","position":6,"is_corresponding":false},{"id":257435,"name":"Kim A. Caldwell","orcid":"0000-0003-1580-6122","position":7,"is_corresponding":false},{"id":257437,"name":"Guy A. Caldwell","orcid":"0000-0002-8283-9090","position":8,"is_corresponding":false},{"id":574635,"name":"J. Brucker Nourse","orcid":"0000-0002-8565-8615","position":0,"is_corresponding":true}],"reference_count":100,"raw_metadata":null,"created_at":"2026-07-19T01:11:44.152490Z","pmid":"36745808","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":[]}