Roles of a novel gene FG01 in inhibiting Alzheimer's amyloid and tau pathologies and GSK3 activity
During the last year we have deciphered the molecular mechanism of Rps23rg1 gene's function. We found that the RPS23RG1 protein interacts with adenylate cyclase proteins and increases the level of the signaling molecule, called cyclic AMP, which, in turn, upregulates the activity of a protein called PKA. Activated PKA adds a phosphate group to GSK-3 and reduces its enzymatic activity, leading to the reduced Abeta generation and tau hyperphosphorylation. This appears to be counteracting the effects seen in AD. Furthermore, we have generated transgenic mice that overexpress the RPS23RG1 protein and crossed them with an AD mouse model (called 3xTg). Our results demonstrated that overexpression of RPS23RG1 protein in the brain can alleviate AD-like pathologies and increase synapse numbers in AD mice. These results have been published in the scientific journal, Neuron (Zhang et al. 2009). More recently, we identified one Rps23rg1 homolog, Rps23rg2, that performs similar function to that of Rps23rg1 in reducing Abeta generation and tau hyperphosphorylation. In addition, we demonstrated that the transmembrane domain of RPS23RG1 is crucial for its function. The new results have just been accepted for publication in the scientific journal, Human Molecular Genetics (Huang et al. 2010).
Alzheimer's disease is one of the most important subjects of medical research today and so far there is no cure or meaningful effective treatment for this disease. Significant efforts in treating AD have targeted either Abeta generation or tau phosphorylation, but with little success so far. We believe that our study, which identifies the novel Rps23rg gene family members and the molecular mechanism by which their protein products reduce both Abeta generation and tau phosphorylation, bears a significant impact on basic research and on developing new strategies for treating AD.
First published on: June 10, 2008
Last modified on: March 29, 2011