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

• Type of Material: Article
• Authors: Chadwick Hales, Emory University; Eric B Dammer, Emory University; Ian Diner, Emory University; Hong Yi, Emory University; Nicholas Seyfried, Emory University; Marla Gearing, Emory University; Jonathan D Glass, Emory University; Thomas J. Montine, University of Washington; Allan I Levey, Emory University; James J Lah, Emory University
• Language: English
• Date: 2014-07-01
• Publisher: Wiley: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2014 International Society of Neuropathology.
• Final Published Version (URL): http://dx.doi.org/10.1111/bpa.12133
• Title of Journal or Parent Work: Brain Pathology
• ISSN: 1015-6305
• Volume: 24
• Issue: 4
• Start Page: 344
• End Page: 351
• Grant/Funding Information: E.B.D. was supported by a NRSA F32 grant from the NIA (AG038259).; 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).
• Keywords: EXPRESSION; quantitative PCR; ALS; CORTEX; U1; Clinical Neurology; Neurosciences & Neurology; Life Sciences & Biomedicine; Science & Technology; 2,2,7-trimethylguanosine; TAU; Alzheimer's disease; RNA spliceosome; snRNA; Pathology; RNA-BINDING PROTEINS; Neurosciences
• Research Categories: Biology, Neuroscience; Psychology, Cognitive

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.