| First Author | Gómez-Sintes R | Year | 2007 |
| Journal | EMBO J | Volume | 26 |
| Issue | 11 | Pages | 2743-54 |
| PubMed ID | 17510631 | Mgi Jnum | J:122627 |
| Mgi Id | MGI:3714894 | Doi | 10.1038/sj.emboj.7601725 |
| Citation | Gomez-Sintes R, et al. (2007) Neuronal apoptosis and reversible motor deficit in dominant-negative GSK-3 conditional transgenic mice. EMBO J 26(11):2743-54 |
| abstractText | Increased glycogen synthase kinase-3 (GSK-3) activity is believed to contribute to the etiology of chronic disorders like Alzheimer's disease and diabetes, thus supporting therapeutic potential of GSK-3 inhibitors. However, sustained GSK-3 inhibition might induce tumorigenesis through beta-catenin-APC dysregulation. Besides, sustained in vivo inhibition by genetic means (constitutive knock-out mice) revealed unexpected embryonic lethality due to massive hepatocyte apoptosis. Here, we have generated transgenic mice with conditional (tetracycline system) expression of dominant-negative-GSK-3 as an alternative genetic approach to predict the outcome of chronic GSK-3 inhibition, either per se, or in combination with mouse models of disease. By choosing a postnatal neuron-specific promoter, here we specifically address the neurological consequences. Tet/DN-GSK-3 mice showed increased neuronal apoptosis and impaired motor coordination. Interestingly, DN-GSK-3 expression shut-down restored normal GSK-3 activity and re-established normal incidence of apoptosis and motor coordination. These results reveal the importance of intact GSK-3 activity for adult neuron viability and physiology and warn of potential neurological toxicity of GSK-3 pharmacological inhibition beyond physiological levels. Interestingly, the reversibility data also suggest that unwanted side effects are likely to revert if excessive GSK-3 inhibition is halted. |
