{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T20:04:31Z","timestamp":1792008271796,"version":"4.4.0"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"41","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2013,10,8]]},"abstract":"<jats:p>\n                    Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of \u03b2-amyloid and tau in Alzheimer\u2019s disease (AD) has facilitated advancement of the amyloid cascade and tau hypotheses that have dominated AD pathogenesis research and therapeutic development. However, the underlying etiology of the disease remains to be fully elucidated. Here we report a comprehensive study of the human brain-insoluble proteome in AD by mass spectrometry. We identify 4,216 proteins, among which 36 proteins accumulate in the disease, including U1-70K and other U1 small nuclear ribonucleoprotein (U1 snRNP) spliceosome components. Similar accumulations in mild cognitive impairment cases indicate that spliceosome changes occur in early stages of AD. Multiple U1 snRNP subunits form cytoplasmic tangle-like structures in AD but not in other examined neurodegenerative disorders, including Parkinson disease and frontotemporal lobar degeneration. Comparison of RNA from AD and control brains reveals dysregulated RNA processing with accumulation of unspliced RNA species in AD, including myc box-dependent-interacting protein 1, clusterin, and presenilin-1\n                    <jats:italic>.<\/jats:italic>\n                    U1-70K knockdown or antisense oligonucleotide inhibition of U1 snRNP increases the protein level of amyloid precursor protein. Thus, our results demonstrate unique U1 snRNP pathology and implicate abnormal RNA splicing in AD pathogenesis.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1310249110","type":"journal-article","created":{"date-parts":[[2013,9,11]],"date-time":"2013-09-11T07:12:44Z","timestamp":1378883564000},"page":"16562-16567","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":327,"title":["U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer\u2019s disease"],"prefix":"10.1073","volume":"110","author":[{"given":"Bing","family":"Bai","sequence":"first","affiliation":[{"name":"Departments of Structural Biology and Developmental Neurobiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chadwick M.","family":"Hales","sequence":"additional","affiliation":[{"name":"Departments of bNeurology,"},{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping-Chung","family":"Chen","sequence":"additional","affiliation":[{"name":"Departments of Structural Biology and Developmental Neurobiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yair","family":"Gozal","sequence":"additional","affiliation":[{"name":"Departments of bNeurology,"},{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric B.","family":"Dammer","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason J.","family":"Fritz","sequence":"additional","affiliation":[{"name":"Departments of bNeurology,"},{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xusheng","family":"Wang","sequence":"additional","affiliation":[{"name":"St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiangwei","family":"Xia","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duc M.","family":"Duong","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Street","sequence":"additional","affiliation":[{"name":"Human Genetics,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Cantero","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Medical Pharmacology and Psychiatry and Behavioral Sciences, University of California, Los Angeles, CA 91301;"},{"name":"Departmento de Fisiolog\u00eda M\u00e9dica y Biof\u00edsica and Centro de Investigaci\u00f3n Biom\u00e9dica en Red sobre Enfermedades Neurodegenerativas, Instituto de Biomedicina de Sevilla, University Hospital Virgen del Roc\u00edo, University of Sevilla, 41013 Seville, Spain;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Cheng","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Drew R.","family":"Jones","sequence":"additional","affiliation":[{"name":"Departments of Structural Biology and Developmental Neurobiology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiping","family":"Wu","sequence":"additional","affiliation":[{"name":"Departments of Structural Biology and 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60612;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Department of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas J.","family":"Montine","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Washington, Seattle, WA 98104; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas T.","family":"Seyfried","sequence":"additional","affiliation":[{"name":"Biochemistry and"},{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas S.","family":"Wingo","sequence":"additional","affiliation":[{"name":"Departments of bNeurology,"},{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi E.","family":"Sun","sequence":"additional","affiliation":[{"name":"Departments of Molecular and Medical Pharmacology and Psychiatry and Behavioral Sciences, University of California, Los Angeles, CA 91301;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Jin","sequence":"additional","affiliation":[{"name":"Human Genetics,"},{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Hanfelt","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics,"},{"name":"Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna M.","family":"Willcock","sequence":"additional","affiliation":[{"name":"Department of Physiology and Sanders\u2013Brown Center on Aging, University of 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