Title

U1 small nuclear ribonucleoprotein complex and RNA splicing alterations in Alzheimer's disease

Document Type

Article

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.

Keywords

RNA-seq, U1A, liquid chromatography-tandem mass spectrometry, premature cleavage and polyadenylation, proteomics

Medical Subject Headings

Alternative Splicing (genetics, physiology); Alzheimer Disease (physiopathology); Blotting, Western; Brain (metabolism); Chromatography, Liquid; Fluorescent Antibody Technique; High-Throughput Nucleotide Sequencing; Humans; Immunohistochemistry; Proteome (genetics, metabolism); Proteomics; Reverse Transcriptase Polymerase Chain Reaction; Ribonucleoprotein, U1 Small Nuclear (metabolism); Spliceosomes (metabolism); Tandem Mass Spectrometry

Publication Date

10-8-2013

Publication Title

Proceedings of the National Academy of Sciences of the United States of America

E-ISSN

1091-6490

Volume

110

Issue

41

First Page

16562

Last Page

7

PubMed ID

24023061

Digital Object Identifier (DOI)

10.1073/pnas.1310249110

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