title: CRMP2 hyperphosphorylation is characteristic of Alzheimer's disease and not a feature common to other neurodegenerative diseases.
abstract: Collapsin response mediator protein 2 (CRMP2) is an abundant brain-enriched protein that regulates neurite outgrowth. It is phosphorylated by Cdk5 and GSK3, and these modifications are abnormally high in the brains of Alzheimer's disease (AD) patients. Increased phosphorylation of CRMP2 is also apparent in mouse models of AD that express mutated AβPP and PSEN1, but not AβPP or tau alone, where it is detectable before the appearance of amyloid plaques and neurofibrillary tangles, suggesting it is an early event in AD pathogenesis. Here, we have extended these observations by showing that CRMP2 is not hyperphosphorylated in mice overexpressing mutated PSEN1 alone, or in cultured neurons treated with soluble, oligomeric Aβ42 peptide. Similarly, CRMP2 phosphorylation was not increased in a mouse model of severe neurodegeneration (PMSC-1 knockout) or in cultured neurons subjected to neurotoxic concentrations of NMDA or staurosporine. Most interestingly, CRMP2 phosphorylation was not increased in frontal cortex from patients with frontotemporal lobar degeneration associated with mutations in MAPT or with Pick bodies. Together, these observations are consistent with the hypothesis that abnormal phosphorylation of CRMP2 is specific to AD and occurs downstream of excessive processing of AβPP, but that neither excessive Aβ42 peptide nor neurotoxicity alone are sufficient to promote hyperphosphorylation.
authors.affiliation: Biomedical Research Institute, University of Dundee, Ninewells Hospital, Dundee, Scotland, UK.
authors.forename: Ritchie
authors.initials: R
authors.lastname: Williamson
authors.forename: Lidy
authors.initials: L
authors.lastname: van Aalten
authors.forename: David M A
authors.initials: DM
authors.lastname: Mann
authors.forename: Bettina
authors.initials: B
authors.lastname: Platt
authors.forename: Florian
authors.initials: F
authors.lastname: Plattner
authors.forename: Lynn
authors.initials: L
authors.lastname: Bedford
authors.forename: John
authors.initials: J
authors.lastname: Mayer
authors.forename: David
authors.initials: D
authors.lastname: Howlett
authors.forename: Alessia
authors.initials: A
authors.lastname: Usardi
authors.forename: Calum
authors.initials: C
authors.lastname: Sutherland
authors.forename: Adam R
authors.initials: AR
authors.lastname: Cole
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D017207:Rats, Sprague-Dawley; D012756:Sheep; D024801:Tauopathies / Q000175:diagnosis / Q000378:metabolism
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; C095114:collapsin response mediator protein-2