Alzheimer's disease (AD) is characterized by extraneuronal plaques consisting of b-amyloid (A?) peptides and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated, paired helical filaments of the microtubule-associated protein, tau. Multiple lines of evidence suggest that overproduction of A? in the brain is a major cause of AD, whereas hyperphosphorylated tau has been found in many neurodegenerative diseases known as tauopathies. Hence, identification of new genes/proteins involved in these processes is a major goal in AD research and may provide potential therapeutic targets. In the previous funding period, we applied the random homozygous gene perturbation (RHGP) technology to screen for genes involved in A? generation and identified a novel mouse gene, Rps23r1(previously named Fg01 in the original submission). Overexpression of the RPS23R1 protein can significantly reduce A? generation, tau phosphorylation and GSK-3 activity. Further in vitro studies showed that RPS23R1 interacts with adenylate cyclases, increasing cAMP synthesis, which upregulates PKA activity. Both activation of PKA and inactivation of GSK-3 are known to inhibit A? generation and GSK-3 inactivation also inhibits tau phosphorylation. The function of Rps23r1 was also demonstrated in transgenic mice expressing brain-specific Rps23r1. Furthermore, the AD-like pathologies of the APP/PS1/tau triple transgenic AD mice were ameliorated and levels of synaptic marker proteins were increased after crossing the mice with the Rps23r1 transgenic mice. Although Rps23r1 is a unique mouse gene, Rps23r1 produces the same phenotype in cells of various species including human. Rps23r1 originated through mouse Rps23 (ribosomal protein S23) mRNA retroposition, a process where mRNA is reintegrated into the genome resulting in gene duplication/evolution. Since Rps23 retroposition also occurred in humans, it is possible that humans possess functional Rps23r1 homologs. Our results suggest that RPS23R1- and functional human RPS23R1 homolog-mediated signaling pathways may play important roles in the pathogenesis of AD and other diseases, such as cancer and diabetes, in which PKA and GSK-3 are crucially involved. Therefore, in this competitive renewal proposal we aim to determine the functional domain(s) of RPS23R1, identify functional human Rps23r1 homologs, further characterize RPS23R1 and its human homologs and decipher mechanisms underlying their effects, specifically inhibition of A generation, tau phosphorylation and modulation of GSK-3 activity. We will cross brain-specific Rps23r1 transgenic mice with AD transgenic (Tg2576 and APP/PS1/tau triple) mice to determine whether Rps23r1 can ameliorate AD-like pathologies and behavioral/cognitive deficits. We will also generate Rps23r1 conditional knockout mice to explore other physiological functions of Rps23r1. The results of these studies are expected to provide important information for developing new strategies to combat AD and other diseases.
Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by extraneuronal plaques resulting from Ab and NFTs caused by tau phosphorylation. Our identification of the novel gene, Rps23r1, and the molecular pathway/mechanism by which it reduces Ab generation and tau phosphorylation, is expected to have a significant impact on basic research and development of new strategies for treating AD.
|Jiang, Shangtong; Li, Yanfang; Zhang, Xian et al. (2014) Trafficking regulation of proteins in Alzheimer's disease. Mol Neurodegener 9:6|
|Wang, Xin; Huang, Timothy; Bu, Guojun et al. (2014) Dysregulation of protein trafficking in neurodegeneration. Mol Neurodegener 9:31|
|Chen, Yaomin; Wang, Bin; Liu, Dan et al. (2014) Hsp90 chaperone inhibitor 17-AAG attenuates A?-induced synaptic toxicity and memory impairment. J Neurosci 34:2464-70|
|Jiang, Shangtong; Li, Yanfang; Zhang, Cuilin et al. (2014) M1 muscarinic acetylcholine receptor in Alzheimer's disease. Neurosci Bull 30:295-307|
|Wang, Xin; Huang, Timothy; Zhao, Yingjun et al. (2014) Sorting nexin 27 regulates A? production through modulating ?-secretase activity. Cell Rep 9:1023-33|
|Zhang, Yun-wu; Chen, Yaomin; Liu, Yun et al. (2013) APP regulates NGF receptor trafficking and NGF-mediated neuronal differentiation and survival. PLoS One 8:e80571|
|Li, Xinxin; Liu, Yiqian; Zheng, Qiuyang et al. (2013) Ferritin light chain interacts with PEN-2 and affects ýý-secretase activity. Neurosci Lett 548:90-4|
|Sun, Liangwu; Zhao, Yingjun; Zhou, Kun et al. (2013) Insufficient ER-stress response causes selective mouse cerebellar granule cell degeneration resembling that seen in congenital disorders of glycosylation. Mol Brain 6:52|
|Wang, Xin; Zhao, Yingjun; Zhang, Xiaofei et al. (2013) Loss of sorting nexin 27 contributes to excitatory synaptic dysfunction by modulating glutamate receptor recycling in Down's syndrome. Nat Med 19:473-80|
|Nakanishi, Nobuki; Ryan, Scott D; Zhang, Xiaofei et al. (2013) Synaptic protein *1-takusan mitigates amyloid-*-induced synaptic loss via interaction with tau and postsynaptic density-95 at postsynaptic sites. J Neurosci 33:14170-83|
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