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: Bing Bai, Chadwick M Hales, Ping-Chung Chen, Yair Gozal, Eric B Dammer, Jason J Fritz, Xusheng Wang, Qiangwei Xia, Duc M Duong, Craig Street, Gloria Cantero, Dongmei Cheng, Drew R Jones, Zhiping Wu, Yuxin Li, Ian Diner, Craig J Heilman, Howard D Rees, Hao Wu, Li Lin, Keith E Szulwach, Marla Gearing, Elliott J Mufson, David A Bennett, Thomas J Montine, Nicholas T Seyfried, Thomas S Wingo, Yi E Sun, Peng Jin, John Hanfelt, Donna M Willcock, Allan Levey, James J Lah, Junmin Peng
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 110 Issue 41 Pg. 16562-7 (Oct 08 2013) ISSN: 1091-6490 [Electronic] United States
• PMID: 24023061 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Proteome
• Ribonucleoprotein, U1 Small Nuclear

Topics

• 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