Increased CRMP-2 Phosphorylation is Observed in Alzheimer’s Disease: Does This Tell Anything about Disease Development?
Pp. 148-170 (23)
Marc P.M. Soutar, Paul Thornhill, Adam R. Cole and Calum Sutherland
Collapsin response mediator protein-2 (CRMP-2) is a physiological substrate
for GSK3 and Cdk5, two protein kinases suggested to exhibit greater activity in
Alzheimer’s disease (AD). Indeed, phosphorylation of CRMP-2, 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-CRMP-2 is found in
neurofibrillary tangles. In mouse models of AD, increased phosphorylation occurs prior
to pathology, and abnormal phosphorylation is not seen in other forms of human
dementia. Although CRMP-2 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 CRMP-2 function, how that is controlled by phosphorylation, what alterations in
molecular mechanisms could lead to the abnormally high CRMP-2 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 CRMP-2
protein kinases in AD. Importantly, we will compare the processes that may contribute
to increased CRMP-2 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.
Biomarker, collapsin response mediator protein, microtubule
transport, neuronal polarity, phosphorylation.
Medical Research Institute, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland, United Kingdom.