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Research Article

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

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, and Junmin Peng
  1. aDepartments of Structural Biology and Developmental Neurobiology and
  2. dSt. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105;
  3. Departments of bNeurology,
  4. eHuman Genetics,
  5. hBiostatistics and Bioinformatics,
  6. iPathology, and
  7. lBiochemistry and
  8. cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
  9. fDepartments of Molecular and Medical Pharmacology and Psychiatry and Behavioral Sciences, University of California, Los Angeles, CA 91301;
  10. gDepartmento de Fisiología Médica y Biofísica and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Biomedicina de Sevilla, University Hospital Virgen del Rocío, University of Sevilla, 41013 Seville, Spain;
  11. jDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612;
  12. kDepartment of Pathology, University of Washington, Seattle, WA 98104; and
  13. mDepartment of Physiology and Sanders–Brown Center on Aging, University of Kentucky, Lexington, KY 40536

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PNAS October 8, 2013 110 (41) 16562-16567; https://doi.org/10.1073/pnas.1310249110
Bing Bai
aDepartments of Structural Biology and Developmental Neurobiology and
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Chadwick M. Hales
Departments of bNeurology,
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Ping-Chung Chen
aDepartments of Structural Biology and Developmental Neurobiology and
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Yair Gozal
Departments of bNeurology,
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Eric B. Dammer
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Jason J. Fritz
Departments of bNeurology,
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Xusheng Wang
dSt. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105;
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Qiangwei Xia
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Duc M. Duong
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Craig Street
eHuman Genetics,
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Gloria Cantero
fDepartments of Molecular and Medical Pharmacology and Psychiatry and Behavioral Sciences, University of California, Los Angeles, CA 91301;
gDepartmento de Fisiología Médica y Biofísica and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Biomedicina de Sevilla, University Hospital Virgen del Rocío, University of Sevilla, 41013 Seville, Spain;
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Dongmei Cheng
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Drew R. Jones
aDepartments of Structural Biology and Developmental Neurobiology and
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Zhiping Wu
aDepartments of Structural Biology and Developmental Neurobiology and
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Yuxin Li
aDepartments of Structural Biology and Developmental Neurobiology and
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Ian Diner
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Craig J. Heilman
Departments of bNeurology,
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Howard D. Rees
Departments of bNeurology,
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Hao Wu
hBiostatistics and Bioinformatics,
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Li Lin
eHuman Genetics,
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Keith E. Szulwach
eHuman Genetics,
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Marla Gearing
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
iPathology, and
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Elliott J. Mufson
jDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612;
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David A. Bennett
jDepartment of Neurological Sciences, Rush University Medical Center, Chicago, IL 60612;
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Thomas J. Montine
kDepartment of Pathology, University of Washington, Seattle, WA 98104; and
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Nicholas T. Seyfried
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
lBiochemistry and
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Thomas S. Wingo
Departments of bNeurology,
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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Yi E. Sun
fDepartments of Molecular and Medical Pharmacology and Psychiatry and Behavioral Sciences, University of California, Los Angeles, CA 91301;
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Peng Jin
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
eHuman Genetics,
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John Hanfelt
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
hBiostatistics and Bioinformatics,
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Donna M. Willcock
mDepartment of Physiology and Sanders–Brown Center on Aging, University of Kentucky, Lexington, KY 40536
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Allan Levey
Departments of bNeurology,
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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  • For correspondence: junmin.peng@stjude.org jlah@emory.edu alevey@emory.edu
James J. Lah
Departments of bNeurology,
cCenter for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322;
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  • For correspondence: junmin.peng@stjude.org jlah@emory.edu alevey@emory.edu
Junmin Peng
aDepartments of Structural Biology and Developmental Neurobiology and
dSt. Jude Proteomics Facility, St. Jude Children's Research Hospital, Memphis, TN 38105;
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  • For correspondence: junmin.peng@stjude.org jlah@emory.edu alevey@emory.edu
  1. Edited by Gideon Dreyfuss, University of Pennsylvania, Philadelphia, PA, and approved August 12, 2013 (received for review May 30, 2013)

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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.

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U1 snRNP and RNA splicing in AD
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
Proceedings of the National Academy of Sciences Oct 2013, 110 (41) 16562-16567; DOI: 10.1073/pnas.1310249110

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U1 snRNP and RNA splicing in AD
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
Proceedings of the National Academy of Sciences Oct 2013, 110 (41) 16562-16567; DOI: 10.1073/pnas.1310249110
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