Identification and characterization of a novel gene that inhibits Alzheimer's amyloid and tau pathology

Huaxi Xu, PhD
Sanford-Burnham Medical Research Institute' (La Jolla, CA)
Year Awarded:
2008
Grant Duration:
April 1, 2008 to September 30, 2011
Disease:
Alzheimer's Disease
Award Amount:
$400,000
Grant Reference ID:
A2008141
Award Type:
Standard
Award Region:
US Southwestern
In memory of Marion Ahlstrom Hoffman
Huaxi Xu, PhD

Roles of a novel gene FG01 in inhibiting Alzheimer's amyloid and tau pathologies and GSK3 activity

Summary

This investigator has discovered a novel gene, FG01, that can significantly reduce ABeta by interfering with gamma secretase. However, this is accomplished without side effects caused by inhibiting other gamma-secretase activities. This project will continue to characterize the functions of this gene to understand its mechanism of action, and may eventually be applied to develop therapeutic interventions specifically inhibiting ABeta without unwanted side-effects.

Details

Too much of beta-amyloid (ABeta) protein in the brain is believed to initiate the pathological cascade culminating in Alzheimer's disease (AD) - the most common form of dementia. ABeta is derived from the proteolytic cleavage of beta-amyloid precursor protein by beta- and gamma-secretase activities. Inhibiting either secretase is a major goal in AD therapeutics. The gamma-secretase, which determines the generation of the toxic form of ABeta, can be regulated by many factors or genetic pathways. Because gamma-secretase can also cleave a variety of membrane proteins, which are important for normal physiological activities, significant unwanted effects may appear if we could develop drugs to inhibit the gamma-secretase. In this proposal, we utilized a technology called Random Homozygous Knockout to identify genes that can inhibit the gamma-secretase activity and hence reduce brain ABeta levels. Through years of intensive research, we have found a novel gene, FG01, that can significantly reduce ABeta without affecting the action of gamma-secretase toward other important proteins when it is expressed in mouse and human neuron-like cells. We will continue to characterize the functions of this gene to understand its mechanism of action, which may eventually be applied to develop therapeutic interventions specifically inhibiting ABeta without unwanted side-effects.

Research Updates

Overproduction of beta-amyloid protein (Abeta) and hyperphosphorylation of tau protein are two major events in the pathogenesis of Alzheimer's disease (AD). Hyperphosphorylation means that there are too many chemical “phosphate” groups that have been attached to the protein, disrupting its normal functions. We have identified a novel gene, Rps23rg1 (previously called Fg01 and then Rps23r1), whose protein product inhibits both Abeta generation and tau hyperphosphorylation, thus making it a candidate for future treatment of AD. Our purpose of this project is to further characterize Rps23rg1 and determine how this gene is involved in cellular signaling pathways.

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.

Publications

Zhang, Y-w., Liu, L., Zhang, X., Li, W-B., Chen, Y., Huang, X., Sun, L., Luo, W-j., Netzer, W.J., Threadgill, R., Wiegand, G., Wang, R., Cohen, S.N., Greengard, P., Liao, F-F., Li, L., and Xu, H. (2009) A Functional Mouse Retroposed Gene Rps23r1 Inhibits Alzheimer's -Amyloid Generation and Tau Phosphorylation. Neuron. 64(3):328-340.  

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