Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease

Mokhtar, S, Kim, M, Magee, K, Mun Aui, P, Thomas, S, Bakhuraysah, M, Alrehaili, A, Young Lee, J, Steer, D, Kenny, R, McLean, C, Azari, M, Birpanagos, A, Lipiec, E, Heraud, P, Wood, B and Petratos, S 2018, 'Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease', Neural Regeneration Research, vol. 13, no. 6, pp. 1066-1080.


Document type: Journal Article
Collection: Journal Articles

Title Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease
Author(s) Mokhtar, S
Kim, M
Magee, K
Mun Aui, P
Thomas, S
Bakhuraysah, M
Alrehaili, A
Young Lee, J
Steer, D
Kenny, R
McLean, C
Azari, M
Birpanagos, A
Lipiec, E
Heraud, P
Wood, B
Petratos, S
Year 2018
Journal name Neural Regeneration Research
Volume number 13
Issue number 6
Start page 1066
End page 1080
Total pages 15
Publisher Medknow Publications and Media Pvt. Ltd.
Abstract Alzheimers disease (AD) is a neurodegenerative disorder characterized by accumulation of amyloid plaques and neurofibrillary tangles. Prior to the development of these characteristic pathological hallmarks of AD, anterograde axonal transport is impaired. However, the key proteins that initiate these intracellular impairments remain elusive. The collapsin response mediator protein-2 (CRMP-2) plays an integral role in kinesin-1-dependent axonal transport and there is evidence that phosphorylation of CRMP-2 releases kinesin-1. Here, we tested the hypothesis that amyloid-beta (Aβ)-dependent phosphorylation of CRMP-2 disrupts its association with the kinesin-1 (an anterograde axonal motor transport protein) in AD. We found that brain sections and lysates from AD patients demonstrated elevated phosphorylation of CRMP-2 at the T555 site. Additionally, in the transgenic Tg2576 mouse model of familial AD (FAD) that exhibits Aβ accumulation in the brain with age, we found substantial co-localization of pT555CRMP-2 and dystrophic neurites. In SH-SY5Y differentiated neuronal cultures, Aβ-dependent phosphorylation of CRMP-2 at the T555 site was also elevated and this reduced the CRMP-2 association with kinesin-1. The overexpression of an unphosphorylatable form of CRMP-2 in neurons promoted the re-establishment of CRMP-2-kinesin association and axon elongation. These data suggest that Aβ-dependent phosphorylation of CRMP-2 at the T555 site may directly impair anterograde axonal transport protein function, leading to neuronal defects.
Subject Central Nervous System
Keyword(s) amyloid-beta protein
collapsin response mediator protein
kinases
kinesin
microtubules
tubulin
DOI - identifier 10.4103/1673-5374.233451
Copyright notice © 2018 Medknow Publications. All rights reserved.
ISSN 1673-5374
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