{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:24:27Z","timestamp":1781108667710,"version":"3.54.1"},"reference-count":15,"publisher":"National Academy of Sciences","issue":"46","license":[{"start":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T00:00:00Z","timestamp":1762992000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,18]]},"abstract":"<jats:p>\n                    Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the\n                    <jats:italic toggle=\"yes\">C9orf72<\/jats:italic>\n                    gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS\/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2\u03b1 kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2\u03b1 signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2514182122","type":"journal-article","created":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T18:52:58Z","timestamp":1763059978000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["MARK2 regulates C9orf72 repeat\u2013associated non-AUG translation"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8176-2108","authenticated-orcid":false,"given":"Yu-Ning","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-7312-2976","authenticated-orcid":false,"given":"Xiangning","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4818-6054","authenticated-orcid":false,"given":"Lindsey","family":"Hayes","sequence":"additional","affiliation":[{"name":"Brain Science Institute and Department of Neurology, Johns Hopkins University School of Medicine","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Feng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University","place":["Baltimore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9115-8708","authenticated-orcid":false,"given":"Jiou","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University","place":["Baltimore"]},{"name":"Department of Neuroscience, School of Medicine, Johns Hopkins 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