GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons

TY - JOUR

T1 - GSK-3 phosphorylation of the Alzheimer epitope within collapsin response mediator proteins regulates axon elongation in primary neurons

AU - Cole, A R

AU - Knebel, A

AU - Morrice, N A

AU - Robertson, L A

AU - Irving, A J

AU - Connolly, Chris N.

AU - Sutherland, Calum

N1 - dc.publisher: American Society for Biochemistry and Molecular Biology This was the first demonstration that the Alzheimer's associated protein CRMP was targeted by GSK3, and detailed the molecular mechanism by which the Alzheimer's associated epitope was generated. The GSK3/CRMP2 interaction became a novel target for Alzheimer's therapy. I was grant holder, designed the experiments and wrote the paper

PY - 2004/11/26

Y1 - 2004/11/26

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.C400412200

DO - 10.1074/jbc.C400412200

M3 - Article

C2 - 15466863

SN - 0021-9258

VL - 279

SP - 50176

EP - 50180

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 48

ER -