{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:14:37Z","timestamp":1785417277250,"version":"3.56.0"},"posted":{"date-parts":[[2026,2,13]]},"group-title":"Neuroscience","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T00:00:00Z","timestamp":1770940800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/01gavpb45","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/02n3ttt92","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01bcmwk98","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/03fsqvg68","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,4,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Nuclear depletion and cytoplasmic aggregation of TDP-43 define a pathological signature across amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer\u2019s disease, and limbic-predominant age-related TDP-43 encephalopathy (LATE). Stress granule persistence and chronic activation of the integrated stress response (ISR) have been proposed to trigger this pathology, yet clinical trials targeting these pathways have failed despite robust target engagement suggesting that the prevailing model may be incomplete. Here, we use a physiologically relevant recurrent hyperthermia paradigm to directly test the relationship between stress granules and TDP-43 pathology\n                  <jats:italic>in vivo<\/jats:italic>\n                  . We find that RNA-binding proteins typically associated with stress granules persist as dynamic, phase-separated cytoplasmic assemblies in spinal motor neurons of both wild-type and mutant TDP-43 mice. These structures resolve spontaneously and are spatially distinct from TDP-43 puncta. Strikingly, in mutant TDP-43 mice with a compromised acute stress granule response, stress exposure provokes TDP-43 nuclear export and cytoplasmic deposition, culminating in selective loss of spinal \u03b1-motor neurons after recurrent stress. Our results reveal that TDP-43 nuclear clearance and cytoplasmic aggregation can occur independently of stress granules\n                  <jats:italic>in vivo<\/jats:italic>\n                  , overturning a central assumption of TDP-43 pathogenesis. This paradigm shift reframes the mechanistic link between cellular stress and TDP-43 pathology, providing a new perspective for therapeutic strategies related to ISR modulation.\n                <\/jats:p>","DOI":"10.64898\/2026.02.11.705439","type":"posted-content","created":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T08:15:18Z","timestamp":1771056918000},"source":"Crossref","is-referenced-by-count":0,"title":["TDP-43 pathology is linked to motor neuron loss and is independent of stress granules\n                  <i>in vivo<\/i>"],"prefix":"10.64898","author":[{"given":"Alicia","family":"Dubinski","sequence":"first","affiliation":[{"name":"Department of Neuroscience, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, H3C 3J7, Canada"},{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, Qu\u00e9bec, H2X 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ala","family":"Ferdi","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, H3C 3J7, Canada"},{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, Qu\u00e9bec, H2X 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariam","family":"Choughari","sequence":"additional","affiliation":[{"name":"Department of Neuroscience, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, H3C 3J7, Canada"},{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, Qu\u00e9bec, H2X 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Spence","sequence":"additional","affiliation":[{"name":"Institute of Medical Sciences, University of Aberdeen, Aberdeen, AB25 2ZD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arpita","family":"Adhikary","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, H3C 3J7, Canada"},{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, Qu\u00e9bec, H2X 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolane","family":"Fauchon","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, H3C 3J7, Canada"},{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, Qu\u00e9bec, H2X 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Touati","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, Qu\u00e9bec, H2X 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myriam","family":"Gagn\u00e9","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Universit\u00e9 de Montr\u00e9al, Montr\u00e9al, Qu\u00e9bec, H3C 3J7, Canada"},{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, Qu\u00e9bec, H2X 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martha","family":"Liu","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al (CRCHUM), Montr\u00e9al, Qu\u00e9bec, H2X 0A9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Peyrard","sequence":"additional","affiliation":[{"name":"Centre de Recherche du Centre Hospitalier de l\u2019Universit\u00e9 de Montr\u00e9al 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