Axonal Transport of Amyloid Precursor Protein Is Mediated by Direct Binding to the Kinesin Light Chain Subunit of Kinesin-I

Kamal, Adeela; Stokin, Gorazd B.; Yang, Zhaohaui; Xia, Chun-hong; Goldstein, Lawrence S.B.

doi:10.1016/s0896-6273(00)00124-0

Cited by 489 publications

(416 citation statements)

References 60 publications

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“…33,34 Our time-lapse study, however, revealed that both cargoes were affected by defective anterograde axonal transport when JSAP1 and JLP were ablated (Figures 4a-d), and that these defects were reversed by exogenously expressed WT JSAP1 or JLP, but not by ΔKBD-mutant JSAP1 or JLP (Figure 5b; Supplementary Figure S5b). In addition, expressing JSAP1-LZ, a JSAP1 mutant that is unable to interact with KLC, almost completely rescued the impairment of anterograde axonal APP and mitochondrial transport (Figure 5b).…”

Section: Discussionmentioning

confidence: 91%

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

et al. 2015

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Axonal transport is critical for neuronal development and function, and defective axonal transport has been implicated in neurodegenerative diseases. However, how axonal transport is regulated, or how defective transport leads to neuronal degeneration, remains unclear. Here, we report that c-Jun NH 2 -terminal kinase (JNK)/stress-activated protein kinase-associated protein 1 (JSAP1, also known as JNK-interacting protein 3 (JIP3)) and JNK-associated leucine zipper protein (JLP) are essential for postnatal brain development. Mice with a double-knockout (dKO) in Jsap1 and Jlp in the dorsal telencephalon developed progressive neuron loss. Using a primary neuron culture system with induced disruption of targeted genes, combined with gene rescue experiments, we show that JSAP1 and JLP regulate kinesin-1-dependent axonal transport with functional redundancy. We also show that the binding of JSAP1 and JLP to kinesin-1 heavy chain is crucial for interactions between kinesin-1 and microtubules. Furthermore, we describe a molecular mechanism by which defective kinesin-1-dependent axonal transport in Jsap1:Jlp dKO neurons causes axonal degeneration and subsequent neuronal death. JNK hyperactivation because of increased intra-axonal Ca 2+ in the Jsap1:Jlp dKO neurons was found to mediate both the axonal degeneration and neuronal death, in cooperation with the Ca 2+ -dependent protease calpain. Our results indicate that axonal JNK may relocate to the nucleus in a dynein-dependent manner, where it activates the transcription factor c-Jun, resulting in neuronal death. Taken together, our data establish JSAP1 and JLP as positive regulators of kinesin-1-dependent axonal transport, which prevents neuronal degeneration.

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Section: Discussionmentioning

confidence: 91%

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

et al. 2015

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“…Nonetheless, numerous factors implicated in AD including oxidative stress (de la Monte et al, 2000;Perry and Smith, 1997;Smith et al, 1995), APO e (Tesseur et al, 2000), and APP-L (Torroja et al, 1999) have all been shown to affect axonal transport. The observation that AbPP can serve as a kinesin cargo receptor (Kamal et al, 2000(Kamal et al, , 2001 as well as the inhibition of kinesin-dependent transport by tau overexpression (Ebneth et al, 1998;Stamer et al, 2002) should not be overlooked. It would be interesting to see whether tau overexpression and Al affect intracellular transport via a similar mechanism.…”

Section: Discussionmentioning

confidence: 99%

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

et al. 2004

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Aluminum (Al) compounds are neurotoxic and have been shown to induce experimental neurodegeneration although the mechanism of this effect is unclear. In order to study this neurotoxic effect of Al, we have developed an in vitro model system using Al maltolate and human NT2 cells. Al maltolate at 500 mM caused significant cell death with a 24-h incubation and this toxicity was even more evident after 48 h. Lower doses of Al maltolate were also effective, but required a longer incubation for cell death. Nuclear fragmentation suggestive of apoptosis was observed as early as three hours and increased substantially through 24 h. Chromatin condensation and nuclear fragmentation were confirmed by electron microscopy. In addition, TUNEL positive nuclei were also observed. The release of cytochrome c was demonstrated with Western blot analysis. This in vitro model using human cells adds to our understanding of Al neurotoxicity and could provide insight into the neurodegenerative processes in human disease. #

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“…The binding interaction was mapped to amino acids 867-894 of US11 and the heptad repeat cargobinding domain of kinesin. Satpute-Krishnan et al also showed that amyloid precursor protein, a putative kinesin receptor, 121,122 associates with viral particles during anterograde transport. Similar to retrograde movement, data are accumulating that HSV nucleocapsids and tegument travel separately from envelope components in anterograde transport.…”

Section: Virus Attachment and Entrymentioning

confidence: 98%

HSV trafficking and development of gene therapy vectors with applications in the nervous system

et al. 2005

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Herpes simplex virus type 1 (HSV-1) is a neurotropic doublestranded DNA virus that causes cold sores, keratitis, and rarely encephalitis in humans. Nonpathogenic HSV-1 gene transfer vectors have been generated by elimination of viral functions necessary for replication. The life cycle of the native virus includes replication in epithelial cells at the site of initial inoculation followed by retrograde axonal transport to the nuclei of sensory neurons innervating the area of cutaneous primary infection. In this review, we summarize the current understanding of the molecular basis for HSV cell entry, nuclear transport of the genome, virion egress following replication, and retrograde and anterograde axonal transport in neurons. We discuss how each of these properties has been exploited or modified to allow the generation of gene transfer vectors with particular utility for neurological applications. Recent advances in engineering virus entry have provided proof of principle that vector targeting is possible. Furthermore, significant and potentially therapeutic modifications to the pathological responses to various noxious insults have been demonstrated in models of peripheral nerve disease. These applications exploit the natural axonal transport mechanism of HSV, allowing transgene expression in the cell nucleus within the inaccessible trigeminal ganglion or dorsal root ganglion, following the noninvasive procedure of subcutaneous vector inoculation. These findings demonstrate the importance of understanding basic virology in the design of vector systems and the powerful approach of exploiting favorable properties of the parent virus in the generation of gene transfer vectors. Gene Therapy (2005) 12, 891-901.

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Axonal Transport of Amyloid Precursor Protein Is Mediated by Direct Binding to the Kinesin Light Chain Subunit of Kinesin-I

Cited by 489 publications

References 60 publications

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

Aluminum Maltolate-Induced Toxicity in NT2 Cells Occurs Through Apoptosis and Includes Cytochrome c Release

HSV trafficking and development of gene therapy vectors with applications in the nervous system

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