{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T14:52:24Z","timestamp":1792680744908,"version":"4.5.0"},"reference-count":47,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016036","name":"Health~Holland","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016036","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100018748","name":"Argenx","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100018748","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2025,6,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Intracellular protein aggregation is a hallmark of aging and contributes to pathology in some age\u2010associated diseases. In hereditary adult\u2010onset neuromuscular diseases (NMDs), protein aggregates play a key role in disease onset and progression. The wild\u2010type Poly(A) binding protein nuclear 1 (PABPN1) forms benign nuclear aggregates, whereas a short trinucleotide expansion leads to the formation of pathogenic aggregates, a hallmark of Oculopharyngeal Muscular Dystrophy (OPMD). In OPMD, the mutant PABPN1 causes skeletal muscle weakness. So far, the structural differences between benign and pathogenic protein aggregates and their effects on muscle cell biology remain poorly understood. We employed an array of advanced imaging modalities to explore the morphological differences between nuclear aggregates formed by non\u2010pathogenic and pathogenic PABPN1 variants. Through analyses spanning micro\u2010 to nanoscale, we identified distinct structural features of aggregates formed by wild\u2010type and expanded PABPN1. We demonstrate that these differences were more pronounced in differentiated muscle cells compared to proliferating cells. We further linked the structural features of PABPN1 aggregates to muscle cell biology, namely alterations in mitochondrial function and proteasomal activity. Our findings provide new insights into the structural distinctions between pathogenic and non\u2010pathogenic aggregates and their implications for cellular dysfunction in NMDs.<\/jats:p>","DOI":"10.1096\/fj.202501097r","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T09:46:17Z","timestamp":1750758377000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Polyalanine Expansion in PABPN1 Alters the Structure and Dynamics of Its Nuclear Aggregates in Differentiated Muscle Cells"],"prefix":"10.1096","volume":"39","author":[{"given":"Sander D.","family":"Mallon","sequence":"first","affiliation":[{"name":"Department of Human Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Bos","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vahid","family":"Sheikhhassani","sequence":"additional","affiliation":[{"name":"Medical Systems Biophysics and Bioengineering, Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research, Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milad","family":"Shademan","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenard M.","family":"Voortman","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alireza","family":"Mashaghi","sequence":"additional","affiliation":[{"name":"Medical Systems Biophysics and Bioengineering, Division of Systems Pharmacology and Pharmacy Leiden Academic Centre for Drug Research, Leiden University  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas H.","family":"Sharp","sequence":"additional","affiliation":[{"name":"Department of Cell and Chemical Biology Leiden University Medical Center  Leiden the Netherlands"},{"name":"School of Biochemistry, University of Bristol  Bristol UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3152-1952","authenticated-orcid":false,"given":"Vered","family":"Raz","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Leiden University Medical Center  Leiden the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a004440"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.1090109"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fragi.2022.927630"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glu049"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-0186(02)00196-1"},{"key":"e_1_2_9_7_1","first-page":"487","volume-title":"Polyalanine and Polyglutamine Diseases: Possible Common Mechanisms?","author":"Abu\u2010Baker A.","year":"2006"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng0298-164"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.7217105"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/1531-8249(200011)48:5<798::AID-ANA16>3.0.CO;2-U"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10071375"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.febslet.2010.03.010"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi432"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1177\/22143602241304990"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-018-0302-4"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000003554"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.4161\/nucl.2.3.15736"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.105019"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006531"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2007.02.004"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2003.11.021"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-017-0015-0"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2818.2006.01706.x"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201201140"},{"key":"e_1_2_9_25_1","doi-asserted-by":"crossref","unstructured":"M. G. F.Last L.Abendstein L. M.Voortman andT. H.Sharp \u201cAis: Streamlining Segmentation of Cryo\u2010Electron Tomography Datasets \u201d bioRxiv 2024 https:\/\/doi.org\/10.1101\/2004.2004.586917.","DOI":"10.7554\/eLife.98552.1"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/pro.3943"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2011.06.044"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.foodchem.2024.140178"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddq098"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts648"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi432"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07487-w"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167208"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtbi.2016.07.018"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100567"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.12.011"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/gerona\/glac058"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.hmg.a018924"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.11.004"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2020.03.009"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201612111"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xhgg.2024.100269"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrp.2025.102430"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-017-0020-4"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1005092"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/2044-5040-1-15"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010015"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes6020163"}],"container-title":["The FASEB Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/pdf\/10.1096\/fj.202501097R","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,22]],"date-time":"2025-11-22T14:51:18Z","timestamp":1763823078000},"score":1,"resource":{"primary":{"URL":"https:\/\/faseb.onlinelibrary.wiley.com\/doi\/10.1096\/fj.202501097R"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,24]]},"references-count":47,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,6,30]]}},"alternative-id":["10.1096\/fj.202501097R"],"URL":"https:\/\/doi.org\/10.1096\/fj.202501097r","archive":["Portico"],"relation":{},"ISSN":["0892-6638","1530-6860"],"issn-type":[{"value":"0892-6638","type":"print"},{"value":"1530-6860","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,24]]},"assertion":[{"value":"2025-04-04","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-11","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70748"}}