Increased CRMP2 Phosphorylation is Observed in Alzheimers Disease; Does this Tell us Anything About Disease Development?

Abstract

Collapsin response mediator protein-2 (CRMP2) was recently identified as a physiological substrate for GSK3 and Cdk5, two protein kinases suggested to exhibit greater activity in Alzheimer's disease (AD). Indeed, phosphorylation of CRMP2, at the residues targeted by GSK3 and Cdk5, is relatively high in cortex isolated from human AD brain, as well as in the brains of animal models of AD, while phospho-CRMP2 is found in neurofibrillary tangles. In mouse models of AD, increased phosphorylation occurs prior to pathology. Although CRMP2 has no known enzymatic activity, a great deal of information is appearing on its importance in neuronal development and polarity, as well as in axon growth and guidance. In this mini-review, we examine what is known about CRMP2 function, how that is controlled by phosphorylation, what alterations in molecular mechanisms could lead to the abnormally high CRMP2 phosphorylation in AD, and whether this is likely to be specific to AD or occur in other forms of neurodegeneration. This will include discussion of the evidence for increased GSK3 or Cdk5 activity, for decreased phosphatase activity, or the upregulation of other CRMP2 protein kinases in AD. Importantly, we will compare the processes that may contribute to increased CRMP2 phosphorylation with those known to increase tau hyperphosphorylation in AD, and whether these are likely to be part of disease development or a useful early marker for AD.

Collapsin Response Mediator Proteins (CRMPs) Are a New Class of Microtubule-associated Protein (MAP) That Selectively Interacts with Assembled Microtubules via a Taxol-sensitive Binding Interaction

“…7), but given that GSK3 functions in numerous pathways (68), the MT dynamics likely result from multiple targets including CRMPs. There is consistent evidence that phosphorylation of the CRMP C-terminal region negatively regulates their biological function in various contexts, as reviewed (47,69), which fits with the notion that the primary biological role of CRMPs is MT regulation.…”

“…Hyper-phosphorylated CRMP2 is found in disease states such as Alzheimer disease, where the C-terminal GSK3␤ sites show increased phosphorylation (74,75), and the role of GSK3␤ in promoting neurofibrillary tangles of Alzheimer disease involving Tau has been suggested (47). Tau and CRMP2 share several similarities; both drive MT stabilization, both are substrates of Cdk5 (for priming) and GSK3␤, and both are hyper-phosphorylated in Alzheimer disease (47). The antibody 3F4, which recognizes phosphorylated Tau in Alzheimer disease neurofibrillary tangles, also stains this phospho-CRMP2 (6).…”

“…8A) and across species (47). Phosphorylation of Ser-522 (present in CRMP1, CRMP2, and CRMP4), which is a target of CDK5 and other proline-directed kinases, primes the adjacent sites for GSK3␤ phosphorylation (4,48).…”

Collapsin Response Mediator Protein-2: An Emerging Pathologic Feature and Therapeutic Target for Neurodisease Indications

“…CRMP2 is well documented to be hyperphosphorylated in the AD brain in close association with NFTs, though total, extractable CRMP2 is not affected (the amount of functionally available CRMP2 in AD vs. normal brain is not known) [3,23,[37][38][39][40][41] (Fig. 2).…”

“…In the now classic pathway for CRMP2-mediated growth cone collapse, semaphorin-3A (Sema3A) signaling through its receptors neuropilin-1 (NP-1) and plexin A (PlexA1-3) triggers Rac1 activation, affecting downstream kinases and ultimately activating glycogen synthase kinase 3β (GSK3β) which phosphorylates CRMP2 on Thr-509 and Thr-514 [3][4][5][6][7][8]22]. The GSK3β-mediated CRMP2 phosphorylation is prerequisite upon prior phosphorylation of CRMP2 Ser-522 by cyclin dependent kinase-5 (CDK-5) [3,4,22,23]. In a situation analogous to that of tau protein phosphorylation [24], this CDK-5 "priming" is necessary to allow subsequent GSK3β-mediated phosphorylation events.…”