scholarly journals Phosphorylation of KLC1 modifies interaction with JIP1 and abolishes the enhanced fast velocity of APP transport by kinesin-1

2017 ◽  
Vol 28 (26) ◽  
pp. 3857-3869 ◽  
Author(s):  
Kyoko Chiba ◽  
Ko-yi Chien ◽  
Yuriko Sobu ◽  
Saori Hata ◽  
Shun Kato ◽  
...  
Keyword(s):  
Coiled Coil ◽  
Amyloid Β ◽  
Tetratricopeptide Repeat ◽  
Amyloid Β Protein ◽  
The Novel ◽  
Anterograde Transport ◽  
Interacting Protein ◽  
Protein Precursor ◽  
Kinesin Light Chain ◽  
Β Protein

In neurons, amyloid β-protein precursor (APP) is transported by binding to kinesin-1, mediated by JNK-interacting protein 1b (JIP1b), which generates the enhanced fast velocity (EFV) and efficient high frequency (EHF) of APP anterograde transport. Previously, we showed that EFV requires conventional interaction between the JIP1b C-terminal region and the kinesin light chain 1 (KLC1) tetratricopeptide repeat, whereas EHF requires a novel interaction between the central region of JIP1b and the coiled-coil domain of KLC1. We found that phosphorylatable Thr466 of KLC1 regulates the conventional interaction with JIP1b. Substitution of Glu for Thr466 abolished this interaction and EFV, but did not impair the novel interaction responsible for EHF. Phosphorylation of KLC1 at Thr466 increased in aged brains, and JIP1 binding to kinesin-1 decreased, suggesting that APP transport is impaired by aging. We conclude that phosphorylation of KLC1 at Thr466 regulates the velocity of transport of APP by kinesin-1 by modulating its interaction with JIP1b.

scholarly journals Phosphorylation of multiple sites within an acidic region of Alcadein α is required for kinesin-1 association and Golgi exit of Alcadein α cargo

2017 ◽  
Vol 28 (26) ◽  
pp. 3844-3856 ◽  
Author(s):  
Yuriko Sobu ◽  
Keiko Furukori ◽  
Kyoko Chiba ◽  
Angus C. Nairn ◽  
Masataka Kinjo ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Tetratricopeptide Repeat ◽  
Amyloid Β Protein ◽  
Anterograde Transport ◽  
Protein Precursor ◽  
Kinesin Light Chain ◽  
Disordered Structure ◽  
Β Protein ◽  
Direct Association ◽  
Acidic Region

Alcadein α (Alcα) is a major cargo of kinesin-1 that is subjected to anterograde transport in neuronal axons. Two tryptophan- and aspartic acid-containing (WD) motifs located in its cytoplasmic domain directly bind the tetratricopeptide repeat (TPR) motifs of the kinesin light chain (KLC), which activate kinesin-1 and recruit kinesin-1 to Alcα cargo. We found that phosphorylation of three serine residues in the acidic region located between the two WD motifs is required for interaction with KLC. Phosphorylation of these serine residues may alter the disordered structure of the acidic region to induce direct association with KLC. Replacement of these serines with Ala results in a mutant that is unable to bind kinesin-1, which impairs exit of Alcα cargo from the Golgi. Despite this deficiency, the compromised Alcα mutant was still transported, albeit improperly by vesicles following missorting of the Alcα mutant with amyloid β-protein precursor (APP) cargo. This suggests that APP partially compensates for defective Alcα in anterograde transport by providing an alternative cargo receptor for kinesin-1.

scholarly journals Quantitative analysis of APP axonal transport in neurons: role of JIP1 in enhanced APP anterograde transport

2014 ◽  
Vol 25 (22) ◽  
pp. 3569-3580 ◽  
Author(s):  
Kyoko Chiba ◽  
Masahiko Araseki ◽  
Keisuke Nozawa ◽  
Keiko Furukori ◽  
Yoichi Araki ◽  
...  
Keyword(s):  
Quantitative Analysis ◽  
Axonal Transport ◽  
High Frequency ◽  
Coiled Coil ◽  
Tetratricopeptide Repeat ◽  
The Novel ◽  
Anterograde Transport ◽  
Interacting Protein ◽  
A Site

Alzheimer's β-amyloid precursor protein (APP) associates with kinesin-1 via JNK-interacting protein 1 (JIP1); however, the role of JIP1 in APP transport by kinesin-1 in neurons remains unclear. We performed a quantitative analysis to understand the role of JIP1 in APP axonal transport. In JIP1-deficient neurons, we find that both the fast velocity (∼2.7 μm/s) and high frequency (66%) of anterograde transport of APP cargo are impaired to a reduced velocity (∼1.83 μm/s) and a lower frequency (45%). We identified two novel elements linked to JIP1 function, located in the central region of JIP1b, that interact with the coiled-coil domain of kinesin light chain 1 (KLC1), in addition to the conventional interaction of the JIP1b 11–amino acid C-terminal (C11) region with the tetratricopeptide repeat of KLC1. High frequency of APP anterograde transport is dependent on one of the novel elements in JIP1b. Fast velocity of APP cargo transport requires the C11 domain, which is regulated by the second novel region of JIP1b. Furthermore, efficient APP axonal transport is not influenced by phosphorylation of APP at Thr-668, a site known to be phosphorylated by JNK. Our quantitative analysis indicates that enhanced fast-velocity and efficient high-frequency APP anterograde transport observed in neurons are mediated by novel roles of JIP1b.

scholarly journals Amyloid β Protein Precursor Is Phosphorylated by JNK-1 Independent of, yet Facilitated by, JNK-Interacting Protein (JIP)-1

2003 ◽  
Vol 278 (43) ◽  
pp. 42058-42063 ◽  
Author(s):  
Meir H. Scheinfeld ◽  
Enrico Ghersi ◽  
Peter Davies ◽  
Luciano D'Adamio
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Interacting Protein ◽  
Protein Precursor ◽  
Β Protein

scholarly journals Amyloid-β Oligomers Induce Only Mild Changes to Inhibitory Bouton Dynamics

2021 ◽  
Vol 5 (1) ◽  
pp. 153-160 ◽  
Author(s):  
Marvin Ruiter ◽  
Christine Lützkendorf ◽  
Jian Liang ◽  
Corette J. Wierenga
Keyword(s):  
Hippocampal Slices ◽  
Inhibitory Neuron ◽  
Amyloid Β ◽  
Inhibitory Neurons ◽  
Inhibitory Synapses ◽  
Amyloid Β Protein ◽  
Protein Precursor ◽  
Β Protein ◽  
Plaque Load ◽  
Early Alzheimer’S Disease

The amyloid-β protein precursor is highly expressed in a subset of inhibitory neuron in the hippocampus, and inhibitory neurons have been suggested to play an important role in early Alzheimer’s disease plaque load. Here we investigated bouton dynamics in axons of hippocampal interneurons in two independent amyloidosis models. Short-term (24 h) amyloid-β (Aβ)-oligomer application to organotypic hippocampal slices slightly increased inhibitory bouton dynamics, but bouton density and dynamics were unchanged in hippocampus slices of young-adult AppNL - F - G-mice, in which Aβ levels are chronically elevated. These results indicate that loss or defective adaptation of inhibitory synapses are not a major contribution to Aβ-induced hyperexcitability.

The upstream stimulatory factor functionally interacts with the Alzheimer amyloid β-protein precursor gene

1995 ◽  
Vol 4 (9) ◽  
pp. 1527-1533 ◽  
Author(s):  
Dora M. Kovacs ◽  
Wilma Wasco ◽  
Johanna Witherby ◽  
Kevin M. Felsenstein ◽  
Franck Brunei ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Upstream Stimulatory Factor ◽  
Protein Precursor ◽  
Β Protein ◽  
Stimulatory Factor
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