{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T19:51:50Z","timestamp":1787601110553,"version":"build-2736575974"},"posted":{"date-parts":[[2025,9,23]]},"group-title":"Cell Biology","reference-count":58,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T00:00:00Z","timestamp":1758585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"award":["Allen Distinguished Investigator Award"],"award-info":[{"award-number":["Allen Distinguished Investigator Award"]}],"id":[{"id":"https:\/\/ror.org\/01degd278","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R35GM134859"],"award-info":[{"award-number":["R35GM134859"]}],"id":[{"id":"https:\/\/ror.org\/04q48ey07","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,23]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Emery-Dreifuss muscular dystrophy (EDMD) arises from mutations in nuclear lamins or emerin. Current pathological models emphasize defects in nuclear mechanics and transcription regulation. Yet these models do not fully explain the complexity of EDMD or other laminopathies. Here, we uncover an emerging pathway linking nuclear lamina defects to the reorganization of cytoplasmic biophysics, revealing how nuclear dysfunction cascades throughout the cell. Using\n                  <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                  EDMD models, we demonstrate that lamin mutations dramatically alter cytoplasmic organization, reducing macromolecular crowding and increasing diffusivity of 40 nm\n                  <jats:underline>G<\/jats:underline>\n                  enetically\n                  <jats:underline>E<\/jats:underline>\n                  ncoded\n                  <jats:underline>M<\/jats:underline>\n                  ultimeric (GEM) nanoparticles. These striking biophysical changes coincide with nuclear positioning defects and collapsed endoplasmic reticulum architecture, mirroring phenotypes associated with ribosome depletion. We propose a mechanism where mutations in the\n                  <jats:italic>C. elegans<\/jats:italic>\n                  lamin\n                  <jats:italic>lmn-1<\/jats:italic>\n                  disrupt nucleolar density and ribosome biogenesis, creating a nucleolar-ribosomal axis that propagates defects from the nucleus to the cytoplasm. Genetic interactions between\n                  <jats:italic>lmn-1<\/jats:italic>\n                  and ribosomes support this regulatory relationship. While individual depletion of other nuclear envelope proteins produces minimal effects, combined loss of the functionally redundant emerin ortholog\n                  <jats:italic>emr-1<\/jats:italic>\n                  and LEM-domain protein\n                  <jats:italic>lem-2<\/jats:italic>\n                  phenocopied\n                  <jats:italic>lmn-1<\/jats:italic>\n                  mutants, demonstrating that cytoplasmic biophysical disruption lies at EDMD\u2019s pathogenic core. Our findings establish a paradigm where nuclear lamina defects fundamentally rewire cellular biophysics through nucleolar-ribosomal dysfunction, opening transformative therapeutic avenues for treating laminopathies.\n                <\/jats:p>","DOI":"10.1101\/2025.09.22.677926","type":"posted-content","created":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T12:35:17Z","timestamp":1758630917000},"source":"Crossref","is-referenced-by-count":3,"title":["Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis controlling cytoplasmic macromolecular crowding"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4831-1274","authenticated-orcid":false,"given":"Xiangyi","family":"Ding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sweta","family":"Kumari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2228-8258","authenticated-orcid":false,"given":"Ellen","family":"Gregory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7339-6606","authenticated-orcid":false,"given":"Daniel A.","family":"Starr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6180-8906","authenticated-orcid":false,"given":"G. 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