Aggregates of Small Nuclear Ribonucleic Acids (snRNAs) in Alzheimer's Disease
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 spliceosom...
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| Published in | Brain pathology (Zurich, Switzerland) Vol. 24; no. 4; pp. 344 - 351 |
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| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Switzerland
Blackwell Publishing Ltd
01.07.2014
John Wiley & Sons, Inc John Wiley and Sons Inc |
| Subjects | |
| Online Access | Get full text |
| ISSN | 1015-6305 1750-3639 1750-3639 |
| DOI | 10.1111/bpa.12133 |
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| 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. |
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| AbstractList | 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. 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. [PUBLICATION ABSTRACT] We recently discovered that protein components of the ribonucleic acid ( RNA ) spliceosome form cytoplasmic aggregates in A lzheimer'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 U 1 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 U 1 snRNA and U 1 small nuclear ribonucleoproteins represent a new pathological hallmark of AD . 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.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. |
| Author | Diner, Ian Glass, Jonathan D. Montine, Thomas J. Lah, James J. Yi, Hong Dammer, Eric B. Gearing, Marla Seyfried, Nicholas T. Levey, Allan I. Hales, Chadwick M. |
| AuthorAffiliation | 4 Robert P. Apkarian Integrated Electron Microscopy Core Emory University Atlanta GA 7 Department of Pathology University of Washington Seattle WA 2 Department of Neurology Emory University School of Medicine Atlanta GA 3 Department of Human Genetics Emory University School of Medicine Atlanta GA 6 Department of Pathology Emory University School of Medicine Atlanta GA 5 Department of Biochemistry Emory University School of Medicine Atlanta GA 1 Center for Neurodegenerative Disease Emory University Atlanta GA |
| AuthorAffiliation_xml | – name: 3 Department of Human Genetics Emory University School of Medicine Atlanta GA – name: 4 Robert P. Apkarian Integrated Electron Microscopy Core Emory University Atlanta GA – name: 1 Center for Neurodegenerative Disease Emory University Atlanta GA – name: 5 Department of Biochemistry Emory University School of Medicine Atlanta GA – name: 6 Department of Pathology Emory University School of Medicine Atlanta GA – name: 2 Department of Neurology Emory University School of Medicine Atlanta GA – name: 7 Department of Pathology University of Washington Seattle WA |
| Author_xml | – sequence: 1 givenname: Chadwick M. surname: Hales fullname: Hales, Chadwick M. email: 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 organization: Center for Neurodegenerative Disease, Emory University, Atlanta, GA – sequence: 2 givenname: Eric B. surname: Dammer fullname: Dammer, Eric B. organization: Department of Neurology, Emory University School of Medicine, Atlanta, GA – sequence: 3 givenname: Ian surname: Diner fullname: Diner, Ian organization: Center for Neurodegenerative Disease, Emory University, GA, Atlanta – sequence: 4 givenname: Hong surname: Yi fullname: Yi, Hong organization: Robert P. Apkarian Integrated Electron Microscopy Core, Emory University, GA, Atlanta – sequence: 5 givenname: Nicholas T. surname: Seyfried fullname: Seyfried, Nicholas T. organization: Center for Neurodegenerative Disease, Emory University, Atlanta, GA – sequence: 6 givenname: Marla surname: Gearing fullname: Gearing, Marla organization: Center for Neurodegenerative Disease, Emory University, Atlanta, GA – sequence: 7 givenname: Jonathan D. surname: Glass fullname: Glass, Jonathan D. organization: Center for Neurodegenerative Disease, Emory University, Atlanta, GA – sequence: 8 givenname: Thomas J. surname: Montine fullname: Montine, Thomas J. organization: Department of Pathology, University of Washington, WA, Seattle – sequence: 9 givenname: Allan I. surname: Levey fullname: Levey, Allan I. organization: Center for Neurodegenerative Disease, Emory University, Atlanta, GA – sequence: 10 givenname: James J. surname: Lah fullname: Lah, James J. organization: Center for Neurodegenerative Disease, Emory University, Atlanta, GA |
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| Copyright | 2014 International Society of Neuropathology 2014 International Society of Neuropathology. Brain Pathology © 2014 International Society of Neuropathology |
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| Keywords | 2,2,7-trimethylguanosine ALS quantitative PCR Alzheimer's disease RNA spliceosome snRNA |
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| Notes | Figure S1. snRNA cytoplasmic aggregates found throughout the AD brain. 2,2,7-TMG immunohistochemistry staining of fixed free-floating AD brain (Braak VI). Sections from hippocampus, temporal, frontal and occipital cortices are shown with black arrows pointing to cytoplasmic aggregates. Scale bar = 10 μm.Figure S2. snRNA aggregates colocalize with other snRNP aggregates in AD post-mortem brain. Immunfluorescence staining of fixed free-floating brain with (A,E) Hoechst, (B,F) 2,2,7-TMG, (C) U1-70k and (G) SmD. Overlay images are shown as well (D,H). White arrow point to overlapping snRNA and snRNPs. Scale bar = 10 μm.Figure S3. snRNA in ALS frontal cortex and spinal cord. Representative examples provided. Fifty micrometer free-floating cryopreserved section from (A) ALS human frontal cortex, (B) control spinal cord, (C) AD spinal cord and (D) ALS spinal cord were immunostained with 2,2,7-TMG cap antibody. Normal nuclear snRNA is present in all cells including motor neurons (B,C,D black arrows). Scale bar = 5 μm.Figure S4. RNA hybridization demonstrates U1-snRNA aggregates in neurons with neurofibrillary tangles. RNA hybridization was performed on an AD free-floating tissue section using biotinylated 2′-O-Me-RNA probe against a 17-nucleotide U1 snRNA-specific sequence. Counterstaining with thioflavin S (green) was applied before mounting slides. Black arrows point to U1 snRNA in a tangle-bearing neuron.Table S1. Demographic information of subjects in this study.Table S2. TaqMan Primer/Probe sets for quantitative PCR. ArticleID:BPA12133 Emory Alzheimer's Disease Research Center-NIA-AG025688 ADRC P50 AG05136 istex:EF30A60F43D02B44B914509A3747A68ABE4F7CBE Emory Neuroscience NINDS Core Facility-P30NS055077 NIA (AG038259) ark:/67375/WNG-GBR9SNTT-N NIAP01AG014449 Robert P. Apkarian Integrated Electron Microscopy Core of Emory University Alzheimer's Association New Investigator Research Award (NIRG-12-242297) ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 |
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| Snippet | We recently discovered that protein components of the ribonucleic acid (RNA) spliceosome form cytoplasmic aggregates in Alzheimer's disease (AD) brain,... We recently discovered that protein components of the ribonucleic acid ( RNA ) spliceosome form cytoplasmic aggregates in A lzheimer's disease ( AD ) brain,... |
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| SubjectTerms | 2,2,7‐trimethylguanosine 7-trimethylguanosine Aged Aged, 80 and over Aggregates ALS Alzheimer Disease - metabolism Alzheimer's disease Brain - metabolism Cytoplasm - metabolism Female Fluorescent Antibody Technique Humans Male Microscopy, Electron, Transmission Middle Aged Neurofibrillary Tangles - metabolism quantitative PCR Real-Time Polymerase Chain Reaction RNA spliceosome RNA, Small Nuclear - metabolism snRNA Spinal Cord - metabolism tau Proteins - metabolism Tauopathies - metabolism |
| Title | Aggregates of Small Nuclear Ribonucleic Acids (snRNAs) in Alzheimer's Disease |
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