Identification of calcium and integrin-binding protein 1 as a novel regulator of production of amyloid ß peptide using CRISPR/Cas9-based screening system.
FASEB J
; 34(6): 7661-7674, 2020 06.
Article
em En
| MEDLINE
| ID: mdl-32307772
ABSTRACT
The aberrant metabolism of amyloid ß peptide (Aß) has been implicated in the etiology of Alzheimer disease (AD). Aß is produced via the sequential cleavage of amyloid precursor protein (APP) by ß- and γ-secretases. However, the precise regulatory mechanism of Aß generation still remains unclear. To gain a better understanding of the molecular mechanism of Aß production, we established a genetic screening method based on the CRISPR/Cas9 system to identify novel regulators of Aß production. We successfully identified calcium and integrin-binding protein 1 (CIB1) as a potential negative regulator of Aß production. The disruption of Cib1 significantly upregulated Aß levels. In addition, immunoprecipitation experiments demonstrated that CIB1 interacts with the γ-secretase complex. Moreover, the disruption of Cib1 specifically reduced the cell-surface localization of mature Nicastrin (Nct), which is a component of the γ-secretase complex, without changing the intrinsic activity of γ-secretase. Finally, we confirmed using the single-cell RNA-seq data in human that CIB1 mRNA level in neuron was decreased in the early stage of AD. Taken together, our results indicate that CIB1 regulates Aß production via controlling the subcellular localization of γ-secretase, suggesting CIB1 is involved in the development of AD.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Ligação ao Cálcio
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Peptídeos beta-Amiloides
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Sistemas CRISPR-Cas
Tipo de estudo:
Diagnostic_studies
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Screening_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article