{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:02:28Z","timestamp":1791813748852,"version":"4.3.4"},"reference-count":71,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:00:00Z","timestamp":1790380800000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Overexpression of \u03b1-synuclein (\u03b1-syn), an inherently disordered protein, triggers chronic activation of the mitochondrial unfolded protein response (UPRmt) pathway in Caenorhabditis elegans with enhanced dopaminergic (DA) neurodegeneration. Introduction of a loss-of-function (lf) mutation in atfs-1, the main transcriptional regulator of the UPRmt, into \u03b1-syn nematodes results in significant neuroprotection from \u03b1-syn-induced DA neuron loss. Using this sensitized neuroprotective background, we performed an F3 forward genetic screen in C. elegans atfs-1(lf) mutants to identify molecular components associated with the modulation of neurodegeneration in \u03b1-syn-expressing DA neurons. Homozygous mutant animals were examined for enhanced neurodegeneration; multiple independent alleles were uncovered. Among these, we identified new nonsense alleles encoding the histone lysine demethylases (H3K27me3) jmjd-1.2 (orthologous to human KDM7A, PHF2, and PHF8) and jmjd-3.1 (homologous to yeast CYC8). Another line carried a nonsense allele of twk-14. This gene encodes a conserved protein termed KCNK12 in mammals that facilitates passive background K+ leak currents to set and stabilize resting membrane potential. To further examine the association of these gene products in DA neurodegeneration, we used neuron-specific RNA interference, mutants, or both. DA neurodegeneration was observed in the \u03b1-syn + atfs-1(lf) background when jmjd-1.2, jmjd-3.1, or twk-14 were individually depleted. These results provide evidence that jmjd-1.2 and jmjd-3.1, which encode previously characterized H3K27me3 demethylases, and the uncharacterized twk-14 gene product, orthologous to human KCNK12, naturally confer protection from \u03b1-syn-induced neurotoxicity.<\/jats:p>","DOI":"10.1093\/g3journal\/jkag273","type":"journal-article","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T08:22:28Z","timestamp":1790410948000},"source":"Crossref","is-referenced-by-count":0,"title":["An\n                    <i>atfs-1<\/i>\n                    loss-of-function screen identifies novel regulators of \u03b1-synuclein toxicity in\n                    <i>Caenorhabditis elegans<\/i>\n                    dopaminergic neurons"],"prefix":"10.1093","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4887-5151","authenticated-orcid":false,"given":"Karolina","family":"Willicott","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama , Tuscaloosa, AL 35487 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6518-1856","authenticated-orcid":false,"given":"Joy D","family":"Iroegbu","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama , Tuscaloosa, AL 35487 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0739-2059","authenticated-orcid":false,"given":"Madeline R","family":"Greene","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama , Tuscaloosa, AL 35487 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8621-2907","authenticated-orcid":false,"given":"Aidan C","family":"Meyers","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama , Tuscaloosa, AL 35487 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6420-1008","authenticated-orcid":false,"given":"Pia Francesca","family":"Scarpino","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama , Tuscaloosa, AL 35487 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-8967-6708","authenticated-orcid":false,"given":"Titus O","family":"Oyetade","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama , Tuscaloosa, AL 35487 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama , Tuscaloosa, AL 35487 ,","place":["United 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