Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-beta accumulation modifier
Back to previous page
| Authors: | Morihara, T; Hayashi, N; Yokokoji, M; Akatsu, H; Silverman, MA; Kimura, N; Sato, M; Saito, Y; Suzuki, T; Yanagida, K; Kodama, TS; Tanaka, T; Okochi, M; Tagami, S; Kazui, H; Kudo, T; Hashimoto, R; Itoh, N; Nishitomi, K; Yamaguchi-Kabata, Y; Tsunoda, T; Takamura, H; Katayama, T; Kimura, R; Kaminoa, K; Hashizume, Y; Takeda, M |
| Year: | 2014 |
| Journal: | Proceedings of the National Academy of Sciences of the United States of America 111: 2638-2643 Article Link (DOI) |
| Title: | Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-beta accumulation modifier |
| Abstract: | Alzheimer's disease (AD) is characterized by the accumulation of amyloid-beta (A beta). The genes that govern this process, however, have remained elusive. To this end, we combined distinct mouse strains with transcriptomics to directly identify disease-relevant genes. We show that AD model mice (APP-Tg) with DBA/2 genetic backgrounds have significantly lower levels of A beta accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress A beta accumulation. To avoid detecting secondarily affected genes by A beta, we used non-Tg mice in the absence of A beta pathology and selected candidate genes differently expressed in DBA/2 mice. Additional transcriptome analysis of APP-Tg mice with mixed genetic backgrounds revealed kinesin light chain-1 (Klc1) as an A beta modifier, indicating a role for intracellular trafficking in A beta accumulation. A beta levels correlated with the expression levels of Klc1 splice variant E and the genotype of Klc1 in these APP-Tg mice. In humans, the expression levels of KLC1 variant E in brain and lymphocyte were significantly higher in AD patients compared with unaffected individuals. Finally, functional analysis using neuroblastoma cells showed that overexpression or knockdown of KLC1 variant E increases or decreases the production of A beta, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of A beta pathology. This unique combination of distinct mouse strains and model mice with transcriptomics is expected to be useful for the study of genetic mechanisms of other complex diseases. |
Departmental members may update their publication list.