Genome-wide, high-content siRNA screening identifies the Alzheimer's genetic risk factor FERMT2 as a major modulator of APP metabolism.
Acta Neuropathol
; 133(6): 955-966, 2017 06.
Article
em En
| MEDLINE
| ID: mdl-27933404
ABSTRACT
Genome-wide association studies (GWASs) have identified 19 susceptibility loci for Alzheimer's disease (AD). However, understanding how these genes are involved in the pathophysiology of AD is one of the main challenges of the "post-GWAS" era. At least 123 genes are located within the 19 susceptibility loci; hence, a conventional approach (studying the genes one by one) would not be time- and cost-effective. We therefore developed a genome-wide, high-content siRNA screening approach and used it to assess the functional impact of gene under-expression on APP metabolism. We found that 832 genes modulated APP metabolism. Eight of these genes were located within AD susceptibility loci. Only FERMT2 (a ß3-integrin co-activator) was also significantly associated with a variation in cerebrospinal fluid Aß peptide levels in 2886 AD cases. Lastly, we showed that the under-expression of FERMT2 increases Aß peptide production by raising levels of mature APP at the cell surface and facilitating its recycling. Taken as a whole, our data suggest that FERMT2 modulates the AD risk by regulating APP metabolism and Aß peptide production.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Precursor de Proteína beta-Amiloide
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RNA Interferente Pequeno
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Proteínas de Membrana
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Proteínas de Neoplasias
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Prognostic_studies
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Risk_factors_studies
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Screening_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Acta Neuropathol
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
França