GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons.
Elevated glycogen synthase kinase-3 (GSK-3) activity is associated with Alzheimer disease. We have found that collapsin response mediator proteins (CRMP) 2 and 4 are physiological substrates of GSK-3. The amino acids targeted by GSK-3 comprise a hyperphosphorylated epitope first identified in plaques isolated from Alzheimer brain. Expression of wild type CRMP2 in primary hippocampal neurons or SH-SY5Y neuroblastoma cells promotes axon elongation. However, a GSK-3-insensitive CRMP2 mutant has dramatically reduced ability to promote axon elongation, a similar effect to pharmacological inhibition of GSK-3. Hence, we propose that phosphorylation of CRMP proteins by GSK-3 regulates axon elongation. This work provides a direct connection between hyperphosphorylation of these residues and elevated GSK-3 activity, both of which are observed in Alzheimer brain.
Cole
Adam R
AR
Division of Pathology and Neurosciences, University of Dundee, Ninewells Hospital, Dundee DD1 9SY, Scotland.
Knebel
Axel
A
Morrice
Nick A
NA
Robertson
Laura A
LA
Irving
Andrew J
AJ
Connolly
Chris N
CN
Sutherland
Calum
C
D000544:Alzheimer Disease / Q000276:immunology*; D000818:Animals; D001369:Axons / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins / Q000276:immunology / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D040121:Semaphorin-3A / Q000276:immunology / Q000378:metabolism*
D000939:Epitopes; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D040121:Semaphorin-3A; C095114:collapsin response mediator protein-2; D038362:Glycogen Synthase Kinase 3