The novel cargo Alcadein induces vesicle association of kinesin-1 motor components and activates axonal transport

Araki, Yasuhisa; Kawano, Takanori; Taru, Hidenori; Saito, Yuhki; Wada, Sohei; Miyamoto, Kanako; Kobayashi, Hiroyoshi; Ishikawa, Hiroyasu; Ohsugi, Yujin; Yamamoto, Tohru; Matsuno, Kenji; Kinjo, Masataka; Suzuki, Toshiharu

doi:10.1038/sj.emboj.7601609

Cited by 140 publications

(245 citation statements)

References 33 publications

(56 reference statements)

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“…In the presence of Alcadein, the APP-JIP-1 complex is released from the KLC, the transport of APP-containing vesicles is inhibited, and the generation of A peptides is increased (Fig. 3) [110]. These results suggest that the transport of APP-containing vesicles by kinesin-1 suppresses the formation of A peptides, whereas the accumulation of stationary or aggregated APP-containing vesicles increases the formation of A peptides.…”

Section: Jip Family Of Proteinsmentioning

confidence: 53%

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Taru

Suzuki

2009

JAD

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Section: Jip Family Of Proteinsmentioning

confidence: 53%

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Taru

Suzuki

2009

JAD

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“…Subsequently, a corresponding variation in the expression levels of KLC1 variant E in sporadic AD in the human population was discovered. These findings, along with other studies (33)(34)(35)(36)(37)(38)(39)41), add a critical element to the understanding of AD etiology and implicate intracellular trafficking as a causative factor in Aβ accumulation. The present study also shows that the combination of animal models and transcriptomics is an effective strategy for identifying unique genes causative in complex human diseases.…”

Section: Discussionmentioning

confidence: 99%

“…These seemingly conflicting results could be explained by splicing of KLC1. The transport of APP requires KLC1 to act as a direct or indirect motor cargo adaptor (35)(36)(37)(38)(39)(40), and changes in the splicing of KLC1 may alter such interactions. Additional studies are required to fully understand the mechanistic role of KLC1 in AD.…”

Section: Discussionmentioning

confidence: 99%

Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-β accumulation modifier

Morita

Hayashi

Yokokoji

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ). 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 Aβ accumulation compared with SJL and C57BL/6 mice. We then applied brain transcriptomics to reveal the genes in DBA/2 that suppress Aβ accumulation. To avoid detecting secondarily affected genes by Aβ, we used non-Tg mice in the absence of Aβ 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 Aβ modifier, indicating a role for intracellular trafficking in Aβ accumulation. Aβ 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 Aβ, respectively. The identification of KLC1 variant E suggests that the dysfunction of intracellular trafficking is a causative factor of Aβ 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.mouse-to-human translation | alternative splicing

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“…The extracellular region of calsyntenin-1 is released into the synaptic cleft, whereas the intracellular region, which can bind Ca 2ϩ , is internalized (13,16). Furthermore, interaction between calsyntenin-1 and kinesin-1 blocked transport of APP-containing vesicles and increased ␤-amyloid generation (17). Despite these pieces of biochemical information, little is known about physiological functions of calsyntenins in vivo.…”

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confidence: 99%

CASY-1, an ortholog of calsyntenins/alcadeins, is essential for learning in Caenorhabditis elegans

Ikeda

Duan

Matsuki

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Calsyntenins/alcadeins are type I transmembrane proteins with two extracellular cadherin domains highly expressed in mammalian brain. They form a tripartite complex with X11/X11L and APP (amyloid precursor protein) and are proteolytically processed in a similar fashion to APP. Although a genetic association of calsyntenin-2 with human memory performance has recently been reported, physiological roles and molecular functions of the protein in the nervous system are poorly understood. Here, we show that CASY-1, the Caenorhabditis elegans ortholog of calsyntenins/ alcadeins, is essential for multiple types of learning. Through a genetic screen, we found that casy-1 mutants show defects in salt chemotaxis learning. casy-1 mutants also show defects in temperature learning, olfactory adaptation, and integration of two sensory signals. casy-1 is widely expressed in the nervous system. Expression of casy-1 in a single sensory neuron and at the postdevelopmental stage is sufficient for its function in salt chemotaxis learning. The fluorescent protein-tagged ectodomain of CASY-1 is released from neurons. Moreover, functional domain analyses revealed that both cytoplasmic and transmembrane domains of this protein are dispensable, whereas the ectodomain, which contains the LG/LNS-like domain, is critically required for learning. These results suggest that learning is modulated by the released ectodomain of CASY-1.ectodomain shedding ͉ learning and memory

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The novel cargo Alcadein induces vesicle association of kinesin-1 motor components and activates axonal transport

Cited by 140 publications

References 33 publications

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Transcriptome analysis of distinct mouse strains reveals kinesin light chain-1 splicing as an amyloid-β accumulation modifier

CASY-1, an ortholog of calsyntenins/alcadeins, is essential for learning in Caenorhabditis elegans

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