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Edited by Gideon Dreyfuss, University of Pennsylvania, Philadelphia, PA, and approved August 12, 2013 (received for review May 30, 2013)
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.
- proteomics
- liquid chromatography-tandem mass spectrometry
- U1A
- RNA-seq
- premature cleavage and polyadenylation
Footnotes
↵1B.B., C.M.H., P.-C.C., and Y.G. contributed equally to this work.
- ↵2To whom correspondence may be addressed. E-mail: junmin.peng{at}stjude.org, jlah{at}emory.edu, or alevey{at}emory.edu.
Author contributions: B.B., C.M.H., Y.G., E.B.D., A.L., J.J.L., and J.P. designed research; B.B., C.M.H., P.-C.C., Y.G., E.B.D., J.J.F., X.W., Q.X., D.M.D., C.S., G.C., D.C., Z.W., Y.L., I.D., C.J.H., H.D.R., L.L., and N.T.S. performed research; M.G., E.J.M., D.A.B., T.J.M., D.M.W., and J.P. contributed new reagents/analytic tools; B.B., C.M.H., P.-C.C., E.B.D., J.J.F., X.W., Q.X., D.M.D., C.S., D.R.J., Z.W., Y.L., H.W., L.L., K.E.S., N.T.S., T.S.W., Y.E.S., P.J., J.H., A.L., J.J.L., and J.P. analyzed data; and B.B., C.M.H., P.-C.C., A.L., J.J.L., and J.P. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
Data deposition: The sequences reported in this paper has been deposited in the ProteomeXchange database, www.proteomexchange.org (identifier PXD000067); and raw RNA-seq files have been deposited in the National Center for Biotechnology Information Sequence Read Archive database, www.ncbi.nlm.nih.gov/sra (accession no. SRA060572).
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1310249110/-/DCSupplemental.
U1 snRNP and RNA splicing in AD
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