{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T03:51:00Z","timestamp":1792036260897,"version":"4.4.0"},"reference-count":37,"publisher":"Wiley","issue":"57","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82271903"],"award-info":[{"award-number":["82271903"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["88201562"],"award-info":[{"award-number":["88201562"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Neuronal intranuclear inclusion disease (NIID) pathogenesis has been strongly linked to uN2CpolyG translated from NOTCH2NLC transcript variant 1. However, emerging evidence suggests that NOTCH2NLC transcript variant 2 may also generate a disease\u2010relevant protein, PolyGN2C\u2010iso2, but isoform\u2010discriminating and antibody\u2010independent evidence remains incomplete.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We characterize the aggregation propensity of PolyGN2C\u2010iso2 in vitro, develop isoform\u2010discriminating monoclonal antibodies for its detection in patient tissues, and perform targeted proteomic analysis of laser\u2010microdissected p62\u2010positive lesion cells. An AAV\u2010mediated mouse model expressing PolyG(108\u00d7)N2C\u2010iso2 is generated to assess its pathogenic potential, followed by behavioral, imaging, histopathological, proteomic, and functional analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>NOTCH2NLC transcript variant 2 generates a distinct protein, PolyGN2C\u2010iso2, which forms aggregates in vitro. Using developed monoclonal antibodies together with targeted proteomics, we provide evidence that PolyGN2C\u2010iso2 is present within the pathognomonic intranuclear inclusions in NIID patient tissues, where it co\u2010localizes with uN2CpolyG. The PolyG(108\u00d7)N2C\u2010iso2 mouse model recapitulates key pathological hallmarks of NIID, including white matter abnormalities and cognitive deficits not fully captured by previous models. Mechanistically, PolyGN2C\u2010iso2 expression is found to induce profound mitochondrial dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings support the possibility that NIID involves a dual\u2010protein pathogenic process involving both uN2CpolyG and PolyGN2C\u2010iso2, which may have implications for therapeutic strategies targeting NOTCH2NLC\u2010derived pathogenic proteins.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/advs.76702","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T12:07:17Z","timestamp":1784808437000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Second Pathogenic Protein, PolyGN2C\u2010iso2, Reveals a Dual\u2010Protein Pathology in Neuronal Intranuclear Inclusion Disease"],"prefix":"10.1002","volume":"13","author":[{"given":"Kang","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology Beijing Tiantan Hospital Capital Medical University  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhao","family":"Ma","sequence":"additional","affiliation":[{"name":"GeneCradle Therapeutics lnc.  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