U1 small nuclear ribonucleoproteins (snRNPs) aggregate in Alzheimer’s disease due to autosomal dominant genetic mutations and trisomy 21

Molecular Neurodegeneration

James J Lah⁵  Allan I Levey⁵  Madhav Thambisetty²  Elliott J Mufson¹  Juan C Troncoso⁴  Marla Gearing⁷  Hong Yi³  Duc Duong⁵  Eric B Dammer⁶  Nicholas T Seyfried⁶  Chadwick M Hales⁵ 

[1] Department of Neurological Sciences, Rush University, Chicago, IL 60612, USA;National Institute of Aging, National Institute of Health, Bethesda, Maryland 20892, USA;Robert P. Apkarian Integrated Electron Microscopy Core, Emory University, Atlanta 30322, Georgia;Departments of Pathology and Neurology, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA;Center for Neurodegenerative Disease, Emory University, Whitehead Research Building, 615 Michael Street, Room 505C, Atlanta 30322, Georgia;Department of Biochemistry, Emory University School of Medicine, Atlanta 30322, Georgia;Department of Pathology, Emory University School of Medicine, Atlanta 30322, Georgia

关键词: Amyloid precursor protein;    Presenilin;    SmD;    U1-70k;    Down syndrome;    Alzheimer’s disease;    snRNP;    Spliceosome;   

Others  :  861587
DOI  :  10.1186/1750-1326-9-15

 received in 2014-01-31, accepted in 2014-04-18,  发布年份 2014

【 摘 要 】

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 β-amyloid processing may influence U1 snRNP aggregate formation.

【 授权许可】

   
2014 Hales et al.; licensee BioMed Central Ltd.

【 图 表 】

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