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

A R Cole, A Knebel, N A Morrice, L A Robertson, A J Irving, Chris N. Connolly, Calum Sutherland

    Research output: Contribution to journalArticle

    203 Citations (Scopus)

    Abstract

    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.
    Original languageEnglish
    Pages (from-to)50176-50180
    Number of pages5
    JournalJournal of Biological Chemistry
    Volume279
    Issue number48
    DOIs
    Publication statusPublished - 26 Nov 2004

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