Increased phosphorylation of collapsin response mediator protein-2 at Thr514 correlates with β-amyloid burden and synaptic deficits in Lewy body dementias.

Huayang Xing,Jasinda H Lee,Yun-An Lim,Mitchell K P Lai,Joyce R Chong,Paul T Francis,Dag Aarsland,Clive G Ballard,Christopher P Chen

doi:10.1186/s13041-016-0264-9

Abstract

Collapsin response mediator protein-2 (CRMP2) regulates axonal growth cone extension, and increased CRMP2 phosphorylation may lead to axonal degeneration. Axonal and synaptic pathology is an important feature of Lewy body dementias (LBD), but the state of CRMP2 phosphorylation (pCRMP2) as well as its correlations with markers of neurodegeneration have not been studied in these dementias. Hence, we measured CRMP2 phosphorylation at Thr509, Thr514 and Ser522, as well as markers of β-amyloid (Aβ), tau-phosphorylation, α-synuclein and synaptic function in the postmortem neocortex of a longitudinally assessed cohort of LBD patients characterized by low (Parkinson’s disease dementia, PDD) and high (dementia with Lewy bodies, DLB) burden of Alzheimer type pathology. We found specific increases of pCRMP2 at Thr514 in DLB, but not PDD. The increased CRMP2 phosphorylation correlated with fibrillogenic Aβ as well as with losses of markers for axon regeneration (β-III-tubulin) and synaptic integrity (synaptophysin) in LBD. In contrast, pCRMP2 alterations did not correlate with tau-phosphorylation or α-synuclein, and also appear unrelated to immunoreactivities of putative upstream kinases glycogen synthase kinase 3β and cyclin-dependent kinase 5, as well as to protein phosphatase 2A. In conclusion, increased pCRMP2 may underlie the axonal pathology of DLB, and may be a novel therapeutic target. However, antecedent signaling events as well as the nature of pCRMP2 association with Aβ and other neuropathologic markers require further study.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-016-0264-9) contains supplementary material, which is available to authorized users.

Highlights

Collapsin response mediator protein-2 (CRMP2) is the first identified member of the collapsin response mediator protein (CRMP) family [1]
We showed in dementia with Lewy bodies (DLB) parietal cortex a specific increase of CRMP2 phosphorylation at Thr514 (Fig. 1), which is known to reduce CRMP2 binding affinity to molecules involved in axonal growth and microtubule dynamics, thereby inhibiting axonal function and leading to axonal pathology [6, 41,42,43,44]
Increased CRMP2 phosphorylation may be one mechanism underlying the detrimental effects of Aβ on synapses in Lewy body dementias (LBD), similar to that seen in Alzheimer’s disease (AD) [16, 17]

Summary

Introduction

Collapsin response mediator protein-2 (CRMP2) is the first identified member of the collapsin response mediator protein (CRMP) family [1]. CRMP2 can be phosphorylated at Ser522 by cyclin-dependent kinase 5 (CDK5), which in turn facilitates glycogen synthase kinase 3β (GSK3β)-mediated phosphorylation at Thr509 and Thr514 [7,8,9,10]. Phosphorylation of CRMP2 decreases CRMP2 binding activity to tubulin, thereby inhibiting neurite outgrowth [10] and potentially leading to axonal degeneration [13], whilst dephosphorylation of CRMP2 by protein phosphatase 2A (PP2A) enhances axonal growth [14]. The neuropathological hallmarks of AD include aggregated β-amyloid (Aβ)-containing senile plaques and neurofibrillary tangles consisting of hyperphosphorylated tau proteins. We measured CRMP2 phosphorylation, Aβ, tau phosphorylation and α-synuclein, together with markers of axonal and synaptic deficits in the postmortem neocortex of a cohort of longitudinally assessed PDD and DLB patients

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