<i>Atlas stumbled</i>: Kinesin light chain‐1 variant E triggers a vicious cycle of axonal transport disruption and amyloid‐β generation in Alzheimer's disease

Gan, Kathlyn J.; Morita, Takashi; Silverman, Michael

doi:10.1002/bies.201400131

Cited by 16 publications

(14 citation statements)

References 120 publications

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“… also suggested that APP‐containing vesicles transported by kinesin‐1 suppressed Aβ generation. Furthermore, recent reports indicated that the kinesin light chain‐1 splice variant E (KLC1vE) is an Aβ accumulation modifier that triggers a vicious cycle of axonal transport disruption in AD . Here, our work demonstrated that KLCs inhibited Aβ 42 aggregation at the single‐molecule level in vitro as determi‐ned by DC‐FCCS.…”

Section: Resultsmentioning

confidence: 60%

Kinesin‐1 inhibits the aggregation of amyloid‐β peptide as detected by fluorescence cross‐correlation spectroscopy

Zheng

Tian

et al. 2016

FEBS Letters

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Although the exact etiology and pathogenesis of Alzheimer's disease (AD) are still unclear, amyloid-b (Ab) generated by the proteolytic processing of amyloid-b precursor protein (APP) aggregate to form toxic amyloid species. Kinesin-1 is the first identified ATP-dependent axonal transport motor protein that has been proven to affect Ab generation and deposition. In this paper, we applied dual-color fluorescence cross-correlation spectroscopy (DC-FCCS) to investigate the direct interaction of Ab with kinesin-1 at the singlemolecule fluorescence level in vitro. The results showed that two kinds of enhanced green fluorescent protein (EGFP)-tagged kinesin light-chain subunits of kinesin-1(KLCs), KLC-E and E-KLC inhibited the aggregation of Ab over a period of time, providing additional insight into the mechanism of axonal transport deficits in AD.

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Section: Resultsmentioning

confidence: 60%

Kinesin‐1 inhibits the aggregation of amyloid‐β peptide as detected by fluorescence cross‐correlation spectroscopy

Zheng

Tian

et al. 2016

FEBS Letters

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“…Audouard et al (101) recently showed that disrupted axonal transport precedes progressive muscle denervation in mice expressing pathogenic human tau, while Stevenson et al (102) used squid giant axon to show that amyloid precursor protein interacts at the organelle/microtubule interface, possibly mediating vesicular transport and Alzheimer's pathology. Gan et al (103) proposed that the disruption of axonal transport by a mutant kinesin light chain-1 splice variant in Alzheimer's disease follows a progression of reduced axonal transport, which leads to accumulation of protein aggregates, followed by an ER stress response. These examples illustrate that the literature is growing at a rapid pace, with novel mechanistic hypotheses pushing the field toward a better understanding of etiology and potential therapeutics.…”

Section: Microtubule Defects In Nervous System Diseasementioning

confidence: 99%

Microtubules in health and degenerative disease of the nervous system

Matamoros

Baas

2016

Brain Research Bulletin

113

112

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Microtubules are essential for the development and maintenance of axons and dendrites throughout the life of the neuron, and are vulnerable to degradation and disorganization in a variety of neurodegenerative diseases. Microtubules, polymers of tubulin heterodimers, are intrinsically polar structures with a plus end favored for assembly and disassembly and a minus end less favored for these dynamics. In the axon, microtubules are nearly uniformly oriented with plus ends out, whereas in dendrites, microtubules have mixed orientations. Microtubules in developing neurons typically have a stable domain toward the minus end and a labile domain toward the plus end. This domain structure becomes more complex during neuronal maturation when especially stable patches of polyaminated tubulin become more prominent within the microtubule. Microtubules are the substrates for molecular motor proteins that transport cargoes toward the plus or minus end of the microtubule, with motor-driven forces also responsible for organizing microtubules into their distinctive polarity patterns in axons and dendrites. A vast array of microtubule-regulatory proteins impart direct and indirect changes upon the microtubule arrays of the neuron, and these include microtubule-severing proteins as well as proteins responsible for the stability properties of the microtubules. During neurodegenerative diseases, microtubule mass is commonly diminished, and the potential exists for corruption of the microtubule polarity patterns and microtubule-mediated transport. These ill effects may be a primary causative factor in the disease or may be secondary effects, but regardless, therapeutics capable of correcting these microtubule abnormalities have great potential to improve the status of the degenerating nervous system.

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“…The recruitment of kinesin-1 to APP via KLC1vE could alter trafficking of APP through the compartments responsible for amyloidogenic cleavage. Alternatively, KLC1vE could more efficiently recruit JNK to APP, and facilitate the phosphorylation conducive of secretase cleavage [70]. These scenarios highlight the numerous ways by which APP transport and processing are entangled.…”

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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Atlas stumbled: Kinesin light chain‐1 variant E triggers a vicious cycle of axonal transport disruption and amyloid‐β generation in Alzheimer's disease

Cited by 16 publications

References 120 publications

Kinesin‐1 inhibits the aggregation of amyloid‐β peptide as detected by fluorescence cross‐correlation spectroscopy

Kinesin‐1 inhibits the aggregation of amyloid‐β peptide as detected by fluorescence cross‐correlation spectroscopy

Microtubules in health and degenerative disease of the nervous system

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

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