title: U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease.
abstract: Deposition of insoluble protein aggregates is a hallmark of neurodegenerative diseases. The universal presence of β-amyloid and tau in Alzheimer's 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. 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.
authors.affiliation: Departments of Structural Biology and Developmental Neurobiology and St. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105.
authors.forename: Bing
authors.initials: B
authors.lastname: Bai
authors.forename: Chadwick M
authors.initials: CM
authors.lastname: Hales
authors.forename: Ping-Chung
authors.initials: PC
authors.lastname: Chen
authors.forename: Yair
authors.initials: Y
authors.lastname: Gozal
authors.forename: Eric B
authors.initials: EB
authors.lastname: Dammer
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Fritz
authors.forename: Xusheng
authors.initials: X
authors.lastname: Wang
authors.forename: Qiangwei
authors.initials: Q
authors.lastname: Xia
authors.forename: Duc M
authors.initials: DM
authors.lastname: Duong
authors.forename: Craig
authors.initials: C
authors.lastname: Street
authors.forename: Gloria
authors.initials: G
authors.lastname: Cantero
authors.forename: Dongmei
authors.initials: D
authors.lastname: Cheng
authors.forename: Drew R
authors.initials: DR
authors.lastname: Jones
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Wu
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Li
authors.forename: Ian
authors.initials: I
authors.lastname: Diner
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Heilman
authors.forename: Howard D
authors.initials: HD
authors.lastname: Rees
authors.forename: Hao
authors.initials: H
authors.lastname: Wu
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Keith E
authors.initials: KE
authors.lastname: Szulwach
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.forename: Elliott J
authors.initials: EJ
authors.lastname: Mufson
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Montine
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Seyfried
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Wingo
authors.forename: Yi E
authors.initials: YE
authors.lastname: Sun
authors.forename: Peng
authors.initials: P
authors.lastname: Jin
authors.forename: John
authors.initials: J
authors.lastname: Hanfelt
authors.forename: Donna M
authors.initials: DM
authors.lastname: Willcock
authors.forename: Allan
authors.initials: A
authors.lastname: Levey
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
mesh_terms: D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology*; D000544:Alzheimer Disease / Q000503:physiopathology*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism*; D002853:Chromatography, Liquid; D005455:Fluorescent Antibody Technique; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007150:Immunohistochemistry; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000378:metabolism*; D017381:Spliceosomes / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D020543:Proteome; D017412:Ribonucleoprotein, U1 Small Nuclear
keywords: RNA-seq; U1A; liquid chromatography-tandem mass spectrometry; premature cleavage and polyadenylation; proteomics
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