Valproic acid is widely used to treat epilepsy and bipolar disorder and is also a potent teratogen, but its mechanisms of action in any of these settings are unknown. We report that valproic acid activates Wntdependent gene expression, similar to lithium, the mainstay of therapy for bipolar disorder. Valproic acid, however, acts through a distinct pathway that involves direct inhibition of histone deacetylase (IC 50 for HDAC1 ؍ 0.4 mM). At therapeutic levels, valproic acid mimics the histone deacetylase inhibitor trichostatin A, causing hyperacetylation of histones in cultured cells. Valproic acid, like trichostatin A, also activates transcription from diverse exogenous and endogenous promoters. Furthermore, valproic acid and trichostatin A have remarkably similar teratogenic effects in vertebrate embryos, while non-teratogenic analogues of valproic acid do not inhibit histone deacetylase and do not activate transcription. Based on these observations, we propose that inhibition of histone deacetylase provides a mechanism for valproic acid-induced birth defects and could also explain the efficacy of valproic acid in the treatment of bipolar disorder.
Alzheimer's disease is associated with increased production and aggregation of amyloid-beta (Abeta) peptides. Abeta peptides are derived from the amyloid precursor protein (APP) by sequential proteolysis, catalysed by the aspartyl protease BACE, followed by presenilin-dependent gamma-secretase cleavage. Presenilin interacts with nicastrin, APH-1 and PEN-2 (ref. 6), all of which are required for gamma-secretase function. Presenilins also interact with alpha-catenin, beta-catenin and glycogen synthase kinase-3beta (GSK-3beta), but a functional role for these proteins in gamma-secretase activity has not been established. Here we show that therapeutic concentrations of lithium, a GSK-3 inhibitor, block the production of Abeta peptides by interfering with APP cleavage at the gamma-secretase step, but do not inhibit Notch processing. Importantly, lithium also blocks the accumulation of Abeta peptides in the brains of mice that overproduce APP. The target of lithium in this setting is GSK-3alpha, which is required for maximal processing of APP. Since GSK-3 also phosphorylates tau protein, the principal component of neurofibrillary tangles, inhibition of GSK-3alpha offers a new approach to reduce the formation of both amyloid plaques and neurofibrillary tangles, two pathological hallmarks of Alzheimer's disease.
Lithium is highly effective in the treatment of bipolar disorder and also has multiple effects on embryonic development, glycogen synthesis, hematopoiesis, and other processes. However, the mechanism of lithium action is still unclear. A number of enzymes have been proposed as potential targets of lithium action, including inositol monophosphatase, a family of structurally related phosphomonoesterases, and the protein kinase glycogen synthase kinase-3. These potential targets are widely expressed, require metal ions for catalysis, and are generally inhibited by lithium in an uncompetitive manner, most likely by displacing a divalent cation. Thus, the challenge is to determine which target, if any, is responsible for a given response to lithium in cells. Comparison of lithium effects with genetic disruption of putative target molecules has helped to validate these targets, and the use of alternative inhibitors of a given target can also lend strong support for or against a proposed mechanism of lithium action. In this review, lithium sensitive enzymes are discussed, and a number of criteria are proposed to evaluate which of these enzymes are involved in the response to lithium in a given setting.
Glycogen synthase kinase-3 (GSK-3) is a critical, negative regulator of diverse signaling pathways. Lithium is a direct inhibitor of GSK-3 and has been widely used to test the putative role of GSK-3 in multiple settings. However, lithium also inhibits other targets, including inositol monophosphatase and structurally related phosphomonoesterases, and thus additional approaches are needed to attribute a given biological effect of lithium to a specific target. For example, lithium is known to increase the inhibitory N-terminal phosphorylation of GSK-3, but the target of lithium responsible for this indirect regulation has not been identified. We have characterized a short peptide derived from the GSK-3 interaction domain of Axin that potently inhibits GSK-3 activity in vitro and in mammalian cells and robustly activates Wnt-dependent transcription, mimicking lithium action. We show here, using the GSK-3 interaction domain peptide, as well as small molecule inhibitors of GSK-3, that lithium induces GSK-3 N-terminal phosphorylation through direct inhibition of GSK-3 itself. Reduction of GSK-3 protein levels, either by RNA interference or by disruption of the mouse GSK-3 gene, causes increased N-terminal phosphorylation of GSK-3, confirming that GSK-3 regulates its own phosphorylation status. Finally, evidence is presented that N-terminal phosphorylation of GSK-3 can be regulated by the GSK-3-dependent protein phosphatase-1⅐inhibitor-2 complex.
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