Journal
MOLECULAR NEURODEGENERATION
Volume 9, Issue -, Pages -Publisher
BMC
DOI: 10.1186/1750-1326-9-15
Keywords
Spliceosome; snRNP; Alzheimer's disease; Down syndrome; U1-70k; SmD; Presenilin; Amyloid precursor protein
Categories
Funding
- Robert P. Apkarian Integrated Electron Microscopy Core of Emory University
- Clinical Research Training Fellowship from the American Brain Foundation
- Emory Alzheimer's Disease Research Center [NIA-AG025688, NIAP01AG14449]
- Emory Neuroscience NINDS Core Facility [P30NS055077]
- University of Washington ADRC [NIA-P50-AG05136]
- Alzheimer's Association New Investigator Research Award [NIRG-12-242297]
- NIA intramural Research Program of the National Institutes of Health
Ask authors/readers for more resources
Background: We recently identified U1 small nuclear ribonucleoprotein (snRNP) tangle-like aggregates and RNA splicing abnormalities in sporadic Alzheimer's disease (AD). However little is known about snRNP biology in early onset AD due to autosomal dominant genetic mutations or trisomy 21 in Down syndrome. Therefore we investigated snRNP biochemical and pathologic features in these disorders. Findings: We performed quantitative proteomics and immunohistochemistry in postmortem brain from genetic AD cases. Electron microscopy was used to characterize ultrastructural features of pathologic aggregates. U1-70k and other snRNPs were biochemically enriched in the insoluble fraction of human brain from subjects with presenilin 1 (PS1) mutations. Aggregates of U1 snRNP-immunoreactivity formed cytoplasmic tangle-like structures in cortex of AD subjects with PS1 and amyloid precursor protein (APP) mutations as well as trisomy 21. Ultrastructural analysis with electron microscopy in an APP mutation case demonstrated snRNP immunogold labeling of paired helical filaments (PHF). Conclusions: These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD. Since dominant genetic mutations and trisomy 21 result in dysfunctional amyloid processing, the findings suggest that aberrant beta-amyloid processing may influence U1 snRNP aggregate formation.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available