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Modeling the ALS\u2010associated Arg812Ter mutation in mice revealed that the resulting truncated Nek1 (Nek1\n                    <jats:sup>t<\/jats:sup>\n                    ) is aggregation\u2010prone, particularly in alpha\u2010motoneurons (\u03b1MNs), and drives canonical ALS symptoms when bi\u2010allelically expressed (\n                    <jats:italic>Nek1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>t\/t<\/jats:italic>\n                    <\/jats:sup>\n                    <jats:italic>)<\/jats:italic>\n                    . Promyelocytic leukemia (\n                    <jats:italic>Pml<\/jats:italic>\n                    ) ablation allows for ALS symptoms to occur even in heterozygote\n                    <jats:italic>Nek1<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>wt\/t<\/jats:italic>\n                    <\/jats:sup>\n                    animals, mimicking the human situation.\n                    <jats:italic>Pml<\/jats:italic>\n                    precludes disease occurrence by promoting SUMO\u2010facilitated degradation of Nek1\n                    <jats:sup>t<\/jats:sup>\n                    proteins through PML nuclear bodies (NBs). Conversely,\n                    <jats:italic>Pml<\/jats:italic>\n                    induction, achieved by activating the interferon pathway via poly(I:C) treatment, clears Nek1\n                    <jats:sup>t<\/jats:sup>\n                    puncta in \u03b1MNs, dramatically reducing ALS\u2010associated symptoms and extending survival by 5\u2009months. Our studies highlight the role of mutant NEK1 expression in ALS pathogenesis and identifies activation of interferon pathways as a candidate therapeutic strategy that promotes\n                    <jats:italic>Pml\u2010<\/jats:italic>\n                    triggered SUMOylation\/degradation of toxic misfolded proteins\n                    <jats:italic>in vivo<\/jats:italic>\n                    , yielding dramatic clinical improvement. These observations provide strong proof\u2010of\u2010concept support to validate PML as a relevant therapeutic target in neurodegenerative conditions associated with protein misfolding and putative aggregation.\n                  <\/jats:p>","DOI":"10.1111\/febs.70487","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T08:24:57Z","timestamp":1773131097000},"page":"5170-5185","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["<i>Pml<\/i>\n                    loss worsens\n                    <scp>NEK1<\/scp>\n                    \u2010linked\n                    <scp>ALS<\/scp>\n                    and\n                    <i>Pml<\/i>\n                    induction drives\n                    <scp>NEK1<\/scp>\n                    degradation, precluding disease 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