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An Alzheimer's disease pathway uncovered by functional omics: the risk gene CELF1 regulates KLC1 splice variant E expression, which drives Aβ pathology

Kikuchi, M.; Viet, J.; Nagata, K.; Sato, M.; David, G.; Audic, Y.; Silverman, M. A.; Yamamoto, M.; Akatsu, H.; Hashizume, Y.; Chiba, K.; Takeda, S.; Akamine, S.; Miyamoto, T.; Uozum, R.; Gotoh, S.; Mori, K.; Ikeda, M.; Paillard, L.; Morihara, T.

2022-03-02 neurology
10.1101/2022.02.28.22271320 medRxiv
Show abstract

In an era when numerous disease-associated genes have been identified, determining the molecular mechanisms of complex diseases is still difficult. The CELF1 region was identified by genome-wide association studies as an Alzheimers disease (AD) risk locus. Using transcriptomics and cross-linking and immunoprecipitation sequencing (CLIP-seq), we found that CELF1, an RNA-binding protein, binds to KLC1 RNA and regulates its splicing. Analysis of two brain banks revealed that CELF1 expression is correlated with inclusion of KLC1 exons downstream of the CELF1-binding region identified by CLIP-seq. In AD, low CELF1 levels result in high levels of KLC1 splice variant E (KLC1_vE), an amyloid-{beta} (A{beta}) pathology-driving gene product. Cell culture experiments confirmed regulation of KLC1_vE by CELF1. Analysis of mouse strains with different propensities for A{beta} accumulation confirmed that Klc1_vE drives A{beta} pathology. Using omics methods, we revealedthe molecular pathway of a complex disease supported by human and mouse genetics.

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