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

Morita, Takashi; Hayashi, Noriyuki; Yokokoji, Mikiko; Akatsu, Hiroyasu; Silverman, Michael; Kimura, Naoko; Saito, Yuhki; Suzuki, Toshiharu; Yanagida, Kanta; Kodama, Takashi; Tanaka, Toshihisa; Okochi, Masayasu; Tagami, Shinji; Kazui, Hiroaki; Kudo, Takashi; Hashimoto, Ryota; Itoh, Naohiro; Nishitomi, Kouhei; Yamaguchi-Kabata, Yumi; Tsunoda, Tatsuhiko; Takamura, Hironori; Katayama, Taiichi; Kimura, Ryo; Kamino, Kouzin; Hashizume, Yoshio; Takeda, Masatoshi

doi:10.1073/pnas.1307345111

Cited by 35 publications

(54 citation statements)

References 46 publications

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“…A recent study found that a variant of KLC1, KLC1vE, confers increased susceptibility to amyloidogenic cleavage of APP, by an unknown mechanism [69]. The recruitment of kinesin-1 to APP via KLC1vE could alter trafficking of APP through the compartments responsible for amyloidogenic cleavage.…”

Section: Factors That Regulate the Transport Of App Also Regulate Itsmentioning

confidence: 99%

Amyloid-β precursor protein: Multiple fragments, numerous transport routes and mechanisms

Mureşan

Muresan

2015

Experimental Cell Research

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This review provides insight into the intraneuronal transport of the Amyloid-β Precursor Protein (APP), the prototype of an extensively posttranslationally modified and proteolytically cleaved transmembrane protein. Uncovering the intricacies of APP transport proves to be a challenging endeavor of cell biology research, deserving increased priority, since APP is at the core of the pathogenic process in Alzheimer’s disease. After being synthesized in the endoplasmic reticulum in the neuronal soma, APP enters the intracellular transport along the secretory, endocytic, and recycling routes. Along these routes, APP undergoes cleavage into defined sets of fragments, which themselves are transported – mostly independently – to distinct sites in neurons, where they exert their functions. We review the currently known routes and mechanisms of transport of full-length APP, and of APP fragments, commenting largely on the experimental challenges posed by studying transport of extensively cleaved proteins. The review emphasizes the interrelationships between the proteolytic and posttranslational modifications, the intracellular transport, and the functions of the APP species. A goal remaining to be addressed in the future is the incorporation of the various views on APP transport into a coherent picture. In this review, the disease context is only marginally addressed; the focus is on the basic biology of APP transport in normal conditions. As shown, the studies of APP transport uncovered numerous mechanisms of transport, some of them conventional, and others, novel, awaiting exploration.

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Section: Factors That Regulate the Transport Of App Also Regulate Itsmentioning

confidence: 99%

Amyloid-β precursor protein: Multiple fragments, numerous transport routes and mechanisms

Mureşan

Muresan

2015

Experimental Cell Research

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“…It is also hijacked by pathogens during infection (3). Accumulating evidence suggests a key role for kinesin-1-dependent MT transport in several neurological disorders including Alzheimer's disease (4). Thus, determining the molecular basis for cargo recognition and regulation of kinesin-1 is important for understanding its role in normal cell function and disease states.…”

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confidence: 99%

The light chains of kinesin-1 are autoinhibited

Yip

Pernigo

Sanger

et al. 2016

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

130

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The light chains (KLCs) of the microtubule motor kinesin-1 bind cargoes and regulate its activity. Through their tetratricopeptide repeat domain (KLC TPR ), they can recognize short linear peptide motifs found in many cargo proteins characterized by a central tryptophan flanked by aspartic/glutamic acid residues (W-acidic). Using a fluorescence resonance energy transfer biosensor in combination with X-ray crystallographic, biochemical, and biophysical approaches, we describe how an intramolecular interaction between the KLC2 TPR domain and a conserved peptide motif within an unstructured region of the molecule, partly occludes the W-acidic binding site on the TPR domain. Cargo binding displaces this interaction, effecting a global conformational change in KLCs resulting in a more extended conformation. Thus, like the motor-bearing kinesin heavy chains, KLCs exist in a dynamic conformational state that is regulated by self-interaction and cargo binding. We propose a model by which, via this molecular switch, W-acidic cargo binding regulates the activity of the holoenzyme.kinesin | KLC | TPR domain | microtubule motor | cytoskeleton

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“…Previously, we (Morihara et al 2014), and others (Jackson et al 2015; Ryman et al 2008; Sebastiani et al 2006), have shown that Aβ accumulation in APP Tg mice with DBA/2 genetic background was significantly lower than those with C57BL/6 and/or SJL. This fact clearly suggests that some genes in DBA/2 suppress Aβ accumulation.…”

Section: Resultsmentioning

confidence: 70%

Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-β accumulation in Alzheimer’s disease

et al. 2018

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Alzheimer’s disease (AD) is a common neurological disease that causes dementia in humans. Although the reports of associated pathological genes have been increasing, the molecular mechanism leading to the accumulation of amyloid-β (Aβ) in human brain is still not well understood. To identify novel genes that cause accumulation of Aβ in AD patients, we conducted an integrative analysis by combining a human genetic association study and transcriptome analysis in mouse brain. First, we examined genome-wide gene expression levels in the hippocampus, comparing them to amyloid Aβ level in mice with mixed genetic backgrounds. Next, based on a GWAS statistics obtained by a previous study with human AD subjects, we obtained gene-based statistics from the SNP-based statistics. We combined p values from the two types of analysis across orthologous gene pairs in human and mouse into one p value for each gene to evaluate AD susceptibility. As a result, we found five genes with significant p values in this integrated analysis among the 373 genes analyzed. We also examined the gene expression level of these five genes in the hippocampus of independent human AD cases and control subjects. Two genes, LBH and SHF, showed lower expression levels in AD cases than control subjects. This is consistent with the gene expression levels of both the genes in mouse which were negatively correlated with Aβ accumulation. These results, obtained from the integrative approach, suggest that LBH and SHF are associated with the AD pathogenesis.Electronic supplementary materialThe online version of this article (10.1007/s00439-018-1906-z) contains supplementary material, which is available to authorized users.

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

Cited by 35 publications

References 46 publications

Amyloid-β precursor protein: Multiple fragments, numerous transport routes and mechanisms

Amyloid-β precursor protein: Multiple fragments, numerous transport routes and mechanisms

The light chains of kinesin-1 are autoinhibited

Integrated analysis of human genetic association study and mouse transcriptome suggests LBH and SHF genes as novel susceptible genes for amyloid-β accumulation in Alzheimer’s disease

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