A functional mouse retroposed gene Rps23r1 reduces Alzheimer's beta-amyloid levels and tau phosphorylation.
Senile plaques consisting of beta-amyloid (Abeta) and neurofibrillary tangles composed of hyperphosphorylated tau are major pathological hallmarks of Alzheimer's disease (AD). Elucidation of factors that modulate Abeta generation and tau hyperphosphorylation is crucial for AD intervention. Here, we identify a mouse gene Rps23r1 that originated through retroposition of ribosomal protein S23. We demonstrate that RPS23R1 protein reduces the levels of Abeta and tau phosphorylation by interacting with adenylate cyclases to activate cAMP/PKA and thus inhibit GSK-3 activity. The function of Rps23r1 is demonstrated in cells of various species including human, and in transgenic mice overexpressing RPS23R1. Furthermore, the AD-like pathologies of triple transgenic AD mice were improved and levels of synaptic maker proteins increased after crossing them with Rps23r1 transgenic mice. Our studies reveal a new target/pathway for regulating AD pathologies and uncover a retrogene and its role in regulating protein kinase pathways.
Zhang
Yun-wu
YW
Institute for Biomedical Research, Xiamen University, Xiamen, China.
Liu
Shijie
S
Zhang
Xue
X
Li
Wu-Bo
WB
Chen
Yaomin
Y
Huang
Xiumei
X
Sun
Liangwu
L
Luo
Wenjie
W
Netzer
William J
WJ
Threadgill
Richard
R
Wiegand
Gordon
G
Wang
Ruishan
R
Cohen
Stanley N
SN
Greengard
Paul
P
Liao
Francesca-Fang
FF
Li
Limin
L
Xu
Huaxi
H
D000262:Adenylyl Cyclases / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D013569:Synapses / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D016229:Amyloid beta-Peptides; C545338:RPS23R1 protein, mouse; D012269:Ribosomal Proteins; D016875:tau Proteins; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D000262:Adenylyl Cyclases