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OCA, Noémie Kunkler, Fabienne Dricot

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 Journal: (2004) Acta Crystallogr.,Sect.D60: 439-446</ref>. GSK-3 phosphorylates a large number of substrates and is himself regulated by phosphorylation,<ref>Neurochem Res. 2007; 32(4-5): 577-595.  Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics, Richard S. Jope,* Christopher J. Yuskaitis, and Eléonore Beurel</ref>.
-GSK-3 is implicated in several diseases like Alzheimer’s disease, diabetes, mood disorders and cancer,<ref>Journal of biological Chemistry 2005:  GSK-3β Directly Phosphorylates and Activates MARK2/PAR-1, Shinichi Kosuga1, Etsu Tashiro1, Toshifumi Kajioka, Mayumi Ueki, Yoshifumi Shimizu and Masaya Imoto2</ref>. In the Alzheimer’s disease, it is thought to be tied to the process of the hyperphosphorylation,<ref> Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M (October 2003). "Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors". J. Mol. Biol. 333 (2): 393-407. doi:10.1016/j.jmb.2003.08.031. PMID 14529625.</ref> of tau proteins which leads to the formation of neurofibrillary tangles and to the build up of Amyloid-β (Aβ) deposits. Dephosphorylated tau binds normally to microtubules, one of the major components of the neuronal cytoskeleton that contributes to the proper function of neurons.
+GSK-3 is implicated in several diseases like Alzheimer’s disease, diabetes, mood disorders and cancer,<ref>Journal of biological Chemistry 2005:  GSK-3β Directly Phosphorylates and Activates MARK2/PAR-1, Shinichi Kosuga1, Etsu Tashiro1, Toshifumi Kajioka, Mayumi Ueki, Yoshifumi Shimizu and Masaya Imoto2</ref>. In the Alzheimer’s disease, it is thought to be tied to the process of the hyperphosphorylation of tau proteins,<ref> Bertrand JA, Thieffine S, Vulpetti A, Cristiani C, Valsasina B, Knapp S, Kalisz HM, Flocco M (October 2003). "Structural characterization of the GSK-3beta active site using selective and non-selective ATP-mimetic inhibitors". J. Mol. Biol. 333 (2): 393-407. doi:10.1016/j.jmb.2003.08.031. PMID 14529625.</ref> which leads to the formation of neurofibrillary tangles and to the build up of Amyloid-β (Aβ) deposits. Dephosphorylated tau binds normally to microtubules, one of the major components of the neuronal cytoskeleton that contributes to the proper function of neurons.
-Considering the roles plaid by GSK3 in promoting both pathological features of Alzheimer disease, GSK3-inhibitors may act positively in the therapy of Alzheimer’s patients. But due to the importance of its role in numerous cellular functions, it is important to develop inhibitors that do not affect or suppress its primary activity,<ref>5 Hu S (Feb 2009). "GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals.". Neurobiol Dis. 33 (2): 193�206. doi:10.1016/j.nbd.2008.10.007. PMID 19038340.</ref>.
+Considering the roles plaid by GSK3 in promoting both pathological features of Alzheimer disease, GSK3-inhibitors may act positively in the therapy of Alzheimer’s patients. But due to the importance of its role in numerous cellular functions, it is important to develop inhibitors that do not affect or suppress its primary activity,<ref>5 Hu S (Feb 2009). "GSK3 inhibitors show benefits in an Alzheimer's disease (AD) model of neurodegeneration but adverse effects in control animals.". Neurobiol Dis. 33 (2): 193-206. doi:10.1016/j.nbd.2008.10.007. PMID 19038340.</ref>.
 There are two isoforms of GSK-3: GSK3α et GSK3. Our concern focuses on GSK3 two mechanisms that affect the activity of the kinase are its inhibition by phosphorylation of serine-9 and its activity enhancement by phosphorylation of tyrosine-216.(3)