Gene-gene functional relationships in Alzheimer’s disease: CELF1 regulates KLC1 alternative splicing - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Biochemical and Biophysical Research Communications Année : 2024

Gene-gene functional relationships in Alzheimer’s disease: CELF1 regulates KLC1 alternative splicing

Masataka Kikuchi
Kenichi Nagata
Masahiro Sato
Hiroyasu Akatsu
Yoshio Hashizume
Shuko Takeda
Shoshin Akamine
Kohji Mori
Manabu Ikeda
Luc Paillard
T Morihara

Résumé

The causes of Alzheimer's disease (AD) are poorly understood, although many genes are known to be involved in this pathology. To gain insights into the underlying molecular mechanisms, it is essential to identify the relationships between individual AD genes. Previous work has shown that the splice variant E of KLC1 (KLC1_vE) promotes AD, and that the CELF1 gene, which encodes an RNA-binding protein involved in splicing regulation, is at a risk locus for AD. Here, we identified a functional link between CELF1 and KLC1 in AD pathogenesis. Transcriptomic data from human samples from different ethnic groups revealed that CELF1 mRNA levels are low in AD brains, and the splicing pattern of KLC1 is strongly correlated with CELF1 expression levels. Specifically, KLC1_vE is negatively correlated with CELF1. Depletion and overexpression experiments in cultured cells demonstrated that the CELF1 protein down-regulates KLC1_vE. In a cross-linking and immunoprecipitation sequencing (CLIP-seq) database, CELF1 directly binds to KLC1 RNA, following which it likely modulates terminal exon usage, hence KLC1_vE formation. These findings reveal a new pathogenic pathway where a risk allele of CELF1 is associated with reduced CELF1 expression, which up-regulates KLC1_vE to promote AD.

Domaines

Génétique
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Dates et versions

hal-04567328 , version 1 (03-05-2024)

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Citer

Masataka Kikuchi, Justine Viet, Kenichi Nagata, Masahiro Sato, Geraldine David, et al.. Gene-gene functional relationships in Alzheimer’s disease: CELF1 regulates KLC1 alternative splicing. Biochemical and Biophysical Research Communications, 2024, pp.150025. ⟨10.1016/j.bbrc.2024.150025⟩. ⟨hal-04567328⟩
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