{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T21:29:36Z","timestamp":1792099776700,"version":"4.4.0"},"reference-count":94,"publisher":"National Academy of Sciences","issue":"7","license":[{"start":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"HHS | NIH | National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R15NS104857"],"award-info":[{"award-number":["R15NS104857"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,2,14]]},"abstract":"<jats:p>\n                    Whole-exome sequencing of Parkinson\u2019s disease (PD) patient DNA identified single-nucleotide polymorphisms (SNPs) in the tyrosine nonreceptor kinase-2 (\n                    <jats:italic>TNK2<\/jats:italic>\n                    ) 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\n                    <jats:italic>TNK2<\/jats:italic>\n                    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\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , 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\n                    <jats:italic>sid-3<\/jats:italic>\n                    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\n                    <jats:italic>TNK2<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2210712120","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T15:24:21Z","timestamp":1675697061000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":14,"title":["Integrated regulation of dopaminergic and epigenetic effectors of neuroprotection in Parkinson\u2019s disease models"],"prefix":"10.1073","volume":"120","author":[{"suffix":"Jr.","given":"J. 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