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

Sara H. Mokhtar, Min Joung Kim, Kylie A. Magee, Pei Mun Aui, Speros Thomas, Maha M. Bakhuraysah, Amani A. Alrehaili, Jae Young Lee, David L. Steer, Rachel Kenny, Catriona McLean, Michael F. Azari, Antonis Birpanagos, Ewlina Lipiec, Philip Heraud, Bayden Wood, Steven Petratos

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Alzheimer's 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.

Original languageEnglish
Article number29926835
Pages (from-to)1066-1080
Number of pages15
JournalNeural Regeneration Research
Volume13
Issue number6
DOIs
Publication statusPublished - 19 Jun 2018

Keywords

  • amyloid-beta protein
  • collapsin response mediator protein
  • kinases
  • kinesin
  • microtubules
  • tubulin

Cite this

Mokhtar, Sara H. ; Kim, Min Joung ; Magee, Kylie A. ; Aui, Pei Mun ; Thomas, Speros ; Bakhuraysah, Maha M. ; Alrehaili, Amani A. ; Lee, Jae Young ; Steer, David L. ; Kenny, Rachel ; McLean, Catriona ; Azari, Michael F. ; Birpanagos, Antonis ; Lipiec, Ewlina ; Heraud, Philip ; Wood, Bayden ; Petratos, Steven. / Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease. In: Neural Regeneration Research. 2018 ; Vol. 13, No. 6. pp. 1066-1080.
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title = "Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease",
abstract = "Alzheimer's 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.",
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author = "Mokhtar, {Sara H.} and Kim, {Min Joung} and Magee, {Kylie A.} and Aui, {Pei Mun} and Speros Thomas and Bakhuraysah, {Maha M.} and Alrehaili, {Amani A.} and Lee, {Jae Young} and Steer, {David L.} and Rachel Kenny and Catriona McLean and Azari, {Michael F.} and Antonis Birpanagos and Ewlina Lipiec and Philip Heraud and Bayden Wood and Steven Petratos",
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Mokhtar, SH, Kim, MJ, Magee, KA, Aui, PM, Thomas, S, Bakhuraysah, MM, Alrehaili, AA, Lee, JY, Steer, DL, Kenny, R, McLean, C, Azari, MF, Birpanagos, A, Lipiec, E, Heraud, P, Wood, B & 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, 29926835, pp. 1066-1080. https://doi.org/10.4103/1673-5374.233451

Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease. / Mokhtar, Sara H.; Kim, Min Joung; Magee, Kylie A.; Aui, Pei Mun; Thomas, Speros; Bakhuraysah, Maha M.; Alrehaili, Amani A.; Lee, Jae Young; Steer, David L.; Kenny, Rachel; McLean, Catriona; Azari, Michael F.; Birpanagos, Antonis; Lipiec, Ewlina; Heraud, Philip; Wood, Bayden; Petratos, Steven.

In: Neural Regeneration Research, Vol. 13, No. 6, 29926835, 19.06.2018, p. 1066-1080.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Amyloid-beta-dependent phosphorylation of collapsin response mediator protein-2 dissociates kinesin in Alzheimer's disease

AU - Mokhtar, Sara H.

AU - Kim, Min Joung

AU - Magee, Kylie A.

AU - Aui, Pei Mun

AU - Thomas, Speros

AU - Bakhuraysah, Maha M.

AU - Alrehaili, Amani A.

AU - Lee, Jae Young

AU - Steer, David L.

AU - Kenny, Rachel

AU - McLean, Catriona

AU - Azari, Michael F.

AU - Birpanagos, Antonis

AU - Lipiec, Ewlina

AU - Heraud, Philip

AU - Wood, Bayden

AU - Petratos, Steven

PY - 2018/6/19

Y1 - 2018/6/19

N2 - Alzheimer's 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.

AB - Alzheimer's 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.

KW - amyloid-beta protein

KW - collapsin response mediator protein

KW - kinases

KW - kinesin

KW - microtubules

KW - tubulin

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DO - 10.4103/1673-5374.233451

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JF - Neural Regeneration Research

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