{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T18:22:19Z","timestamp":1785435739594,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,15]]},"group-title":"Genetics","reference-count":53,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"award":["R03TR004460"],"award-info":[{"award-number":["R03TR004460"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R15NS106460"],"award-info":[{"award-number":["R15NS106460"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Overexpression of \u03b1-synuclein (\u03b1-syn), an inherently disordered protein, triggers chronic activation of the mitochondrial unfolded protein response (UPR\n                  <jats:sup>mt<\/jats:sup>\n                  ) pathway in\n                  <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                  with enhanced dopaminergic (DAergic) neurodegeneration. Introduction of a loss-of-function\n                  <jats:italic>(lf)<\/jats:italic>\n                  mutation in\n                  <jats:italic>atfs-1<\/jats:italic>\n                  , the main transcriptional regulator of the UPR\n                  <jats:sup>mt<\/jats:sup>\n                  , into \u03b1-syn nematodes results in significant neuroprotection from \u03b1-syn-induced DA neuron loss, indicating that compensatory mechanisms provide neuroprotection. We performed a F3 forward genetic screen in\n                  <jats:italic>C. elegans atfs-1(lf)<\/jats:italic>\n                  mutants to identify molecular components associated with the modulation of neurodegeneration via UPR\n                  <jats:sup>mt<\/jats:sup>\n                  signaling 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),\n                  <jats:italic>jmjd-1.2<\/jats:italic>\n                  and\n                  <jats:italic>jmjd-3.1<\/jats:italic>\n                  . Another line carried a nonsense allele of\n                  <jats:italic>twk-14.<\/jats:italic>\n                  This gene encodes a conserved protein termed KCNK12 in mammals that facilitates passive background K\n                  <jats:sup>+<\/jats:sup>\n                  leak currents to set and stabilize resting membrane potential. To further examine the association of these gene products in DA neurodegeneration, mutants and\/or RNA interference were employed. DA neurodegeneration was observed in the \u03b1-syn\n                  <jats:italic>+ atfs-1(lf)<\/jats:italic>\n                  background when\n                  <jats:italic>jmjd-1.2<\/jats:italic>\n                  ,\n                  <jats:italic>jmjd-3.1,<\/jats:italic>\n                  or\n                  <jats:italic>twk-14<\/jats:italic>\n                  were individually depleted. These results provide evidence that\n                  <jats:italic>jmjd-1.2<\/jats:italic>\n                  and\n                  <jats:italic>jmjd-3.1<\/jats:italic>\n                  , which encode previously characterized H3K27me3 demethylases, and the uncharacterized\n                  <jats:italic>twk-14<\/jats:italic>\n                  gene product, orthologous to human KCNK12, naturally confer protection from \u03b1-syn neurotoxicity.\n                <\/jats:p>","DOI":"10.64898\/2026.06.11.731199","type":"posted-content","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T08:40:18Z","timestamp":1781512818000},"source":"Crossref","is-referenced-by-count":0,"title":["A Forward Genetic Screen in\n                  <i>Caenorhabditis elegans<\/i>\n                  for Genes that Modulate \u03b1-synuclein-Induced Neurodegeneration through the Mitochondrial UPR"],"prefix":"10.64898","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, USA"}],"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, USA"}],"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, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aidan 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8283-9090","authenticated-orcid":false,"given":"Guy A.","family":"Caldwell","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA"},{"name":"Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, Heersink School of Medicine, Nathan Shock Center of Excellence in the Basic Biology of Aging, University of Alabama at Birmingham, Birmingham, AL 35294, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1580-6122","authenticated-orcid":false,"given":"Kim A.","family":"Caldwell","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL 35487, USA"},{"name":"Department of Neurology, Center for Neurodegeneration and Experimental Therapeutics, Heersink School of Medicine, 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