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Author Notes:

Corresponding author: Chadwick M. Hales, MD, PhD, Center for Neurodegenerative Disease, Emory University, Whitehead Research Building, 615 Michael Street, Room 505H, Atlanta, GA, 30322 cmhales@emory.edu

C.M.H., E.B.D., N.T.S., A.I.L. and J.J.L. conceived and supervised the project.

H.Y. did electron microscopy.

M.G. and T.J.M. provided human samples.

J.D.G. assisted with pathological interpretation.

I.D. performed protein blots.

C.M.H. performed all immunohistochemistry and qRT-PCR.

E.B.D. performed the RNA hybridization.

C.M.H., E.B.D., N.T.S., J.J.L. and A.I.L. all assisted in writing and editing the paper.

We are grateful for pathological specimens provided by M.G. and T.J.M.

Subjects:

Research Funding:

This research project was supported in part by the Robert P. Apkarian Integrated Electron Microscopy Core of Emory University.

A.I.L.—Emory Alzheimer’s Disease Research Center-NIAAG025688, J.J.L.—NIAP01AG014449, T.J.M.—ADRC P50 AG05136, Emory Neuroscience NINDS Core Facility- P30NS055077.

N.T.S.—Alzheimer’s Association New Investigator Research Award (NIRG-12–242297).

E.B.D. was supported by a NRSA F32 grant from the NIA (AG038259).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences
  • Pathology
  • Neurosciences & Neurology
  • ALS
  • Alzheimer's disease
  • quantitative PCR
  • RNA spliceosome
  • snRNA
  • 2,2,7-trimethylguanosine
  • RNA-BINDING PROTEINS
  • EXPRESSION
  • CORTEX
  • TAU
  • U1

Aggregates of Small Nuclear Ribonucleic Acids (snRNAs) in Alzheimer's Disease

Journal Title:

Brain Pathology

Volume:

Volume 24, Number 4

Publisher:

, Pages 344-351

Type of Work:

Article | Post-print: After Peer Review

Abstract:

We recently discovered that protein components of the ribonucleic acid (RNA) spliceosome form cytoplasmic aggregates in Alzheimer's disease (AD) brain, resulting in widespread changes in RNA splicing. However, the involvement of small nuclear RNAs (snRNAs), also key components of the spliceosome complex, in the pathology of AD remains unknown. Using immunohistochemical staining of post-mortem human brain and spinal cord, we identified cytoplasmic tangle-shaped aggregates of snRNA in both sporadic and familial AD cases but not in aged controls or other neurodegenerative disorders. Immunofluorescence using antibodies reactive with the 2,2,7-trimethylguanosine cap of snRNAs and transmission electron microscopy demonstrated snRNA localization with tau and paired helical filaments, the main component of neurofibrillary tangles. Quantitative real-time polymerase chain reaction (PCR) showed U1 snRNA accumulation in the insoluble fraction of AD brains whereas other U snRNAs were not enriched. In combination with our previous results, these findings demonstrate that aggregates of U1 snRNA and U1 small nuclear ribonucleoproteins represent a new pathological hallmark of AD.

Copyright information:

© 2014 International Society of Neuropathology.

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