Abstract
BackgroundWe 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.FindingsWe 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).ConclusionsThese 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 β-amyloid processing may influence U1 snRNP aggregate formation.
Highlights
We recently identified U1 small nuclear ribonucleoprotein tangle-like aggregates and ribonucleic acid (RNA) splicing abnormalities in sporadic Alzheimer’s disease (AD)
Since dominant genetic mutations and trisomy 21 result in dysfunctional amyloid processing, the findings suggest that aberrant β-amyloid processing may influence U1 small nuclear ribonucleoprotein (snRNP) aggregate formation
RNA sequencing techniques demonstrated widespread RNA splicing dysfunction, including effects on several AD associated genes such as bridging integrator 1 (BIN1) [10], clusterin [11] and presenilin 1 (PS1) [12]. It remains unknown whether the U1 snRNP pathological aggregates are present in genetic forms of AD (PS1 and amyloid precursor protein (APP) mutations or trisomy 21), but such an association would support a link between U1 snRNP abnormalities and aberrant β-amyloid processing mechanisms in AD
Summary
These studies identify U1 snRNP pathologic changes in brain of early onset genetic forms of AD. RNA sequencing techniques demonstrated widespread RNA splicing dysfunction, including effects on several AD associated genes such as bridging integrator 1 (BIN1) [10], clusterin [11] and presenilin 1 (PS1) [12] It remains unknown whether the U1 snRNP pathological aggregates are present in genetic forms of AD (PS1 and APP mutations or trisomy 21), but such an association would support a link between U1 snRNP abnormalities and aberrant β-amyloid processing mechanisms in AD. In addition to the expected nuclear localization, U1-70k labeled cytoplasmic fibrils, and staining of adjacent sections demonstrated Sm-D1 and AT8 labeling of morphologically similar structures with characteristic periodicity of ~80 nm These findings confirm a close association between the snRNP U1-70k and Sm-D1 and pathological aggregates of tau in PHF. Because of the pathologic similarities observed in the immunohistochemistry, we did not feel that pursuing more immunoelectron microscopy experiments would provide additional strength to the study
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
