A Functional Mouse Retroposed Gene Rps23r1 Reduces Alzheimer's β-Amyloid Levels and Tau Phosphorylation

被引：37

作者：

Zhang, Yun-wu ^{[2
,3
,4
]}

Liu, Shijie ^{[4
]}

Zhang, Xue ^{[4
]}

Li, Wu-Bo ^{[1
]}

Chen, Yaomin ^{[4
]}

Huang, Xiumei ^{[2
,3
,4
]}

Sun, Liangwu ^{[4
]}

Luo, Wenjie ^{[5
]}

Netzer, William J. ^{[5
]}

Threadgill, Richard ^{[1
]}

Wiegand, Gordon ^{[1
]}

Wang, Ruishan ^{[2
,3
,4
]}

Cohen, Stanley N. ^{[6
]}

Greengard, Paul ^{[5
]}

Liao, Francesca-Fang ^{[4
,9
]}

Li, Limin ^{[1
,7
,8
]}

Xu, Huaxi ^{[4
]}

机构：

[1] Funct Genet Inc, Gaithersburg, MD 20878 USA

[2] Xiamen Univ, Inst Biomed Res, Xiamen 361005, Peoples R China

[3] Xiamen Univ, Fujian Prov Key Lab Neurodegenerat Dis & Aging Re, Xiamen 361005, Peoples R China

[4] Burnham Inst Med Res, Neurodegenerat Dis Res Program, La Jolla, CA 92037 USA

[5] Rockefeller Univ, Mol & Cellular Neurosci Lab, New York, NY 10065 USA

[6] Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA

[7] Chinese Acad Med Sci, Inst Basic Med Sci, Dept Pathol, Beijing 100005, Peoples R China

[8] Peking Union Med Coll, Beijing 100005, Peoples R China

[9] Univ Tennessee, Dept Pharmacol, Hlth Sci Ctr, Coll Med, Memphis, TN 38163 USA

来源：

NEURON | 2009年 / 64卷 / 03期

基金：

美国国家卫生研究院; 中国国家自然科学基金;

关键词：

PROTEIN-KINASE-A; PRECURSOR PROTEIN; NEOPLASTIC TRANSFORMATION; PROCESSED PSEUDOGENES; RIBOSOMAL-PROTEIN; GSK-3; INHIBITORS; DISEASE; GENERATION; SECRETASE; DEFICIENCY;

D O I：

10.1016/j.neuron.2009.08.036

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Senile plaques consisting of beta-amyloid (A beta) and neurofibrillary tangles composed of hyperphosphorylated tau are major pathological hallmarks of Alzheimer's disease (AD). Elucidation of factors that modulate A beta 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 A beta 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.

引用

页码：328 / 340

页数：13

共 58 条

[1] Unusual phenotypic alteration of β amyloid precursor protein (βAPP) maturation by a new Val-715→Met βAPP-770 mutation responsible for probable early-onset Alzheimer's disease [J].

Ancolio, K ;

Dumanchin, C ;

Barelli, H ;

Warter, JM ;

Brice, A ;

Campion, D ;

Frébourg, T ;

Checler, F .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (07) :4119-4124

[2] Current topics in genome evolution: Molecular mechanisms of new gene formation [J].

Babushok, D. V. ;

Ostertag, E. M. ;

Kazazian, H. H., Jr. .

CELLULAR AND MOLECULAR LIFE SCIENCES, 2007, 64 (05) :542-554

[3] Characterization of new polyclonal antibodies specific for 40 and 42 amino acid long amyloid beta peptides: Their use to examine the cell biology of presenilins and the immunohistochemistry of sporadic Alzheimer's disease and cerebral amyloid angiopathy cases [J].

Barelli, HL ;

Lebeau, A ;

Vizzavona, J ;

Delaere, P ;

Chevallier, N ;

Drouot, C ;

Marambaud, P ;

Ancolio, K ;

Buxbaum, JD ;

Khorkova, O ;

Heroux, J ;

Sahasrabudhe, S ;

Martinez, J ;

Warter, JM ;

Mohr, M ;

Checler, F .

MOLECULAR MEDICINE, 1997, 3 (10) :695-707

[4] Tau protein isoforms, phosphorylation and role in neurodegenerative disorders [J].

Buée, L ;

Bussière, T ;

Buée-Scherrer, V ;

Delacourte, A ;

Hof, PR .

BRAIN RESEARCH REVIEWS, 2000, 33 (01) :95-130

[5] CALCIUM REGULATES PROCESSING OF THE ALZHEIMER AMYLOID PROTEIN-PRECURSOR IN A PROTEIN-KINASE C-INDEPENDENT MANNER [J].

BUXBAUM, JD ;

RUEFLI, AA ;

PARKER, CA ;

CYPESS, AM ;

GREENGARD, P .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1994, 91 (10) :4489-4493

[6] BACE1 is the major β-secretase for generation of Aβ peptides by neurons [J].

Cai, HB ;

Wang, YS ;

McCarthy, D ;

Wen, HJ ;

Borchelt, DR ;

Price, DL ;

Wong, PC .

NATURE NEUROSCIENCE, 2001, 4 (03) :233-234

[7] Carboxyl-terminal fragments of Alzheimer β-amyloid precursor protein accumulate in restricted and unpredicted intracellular compartments in presenilin 1-deficient cells [J].

Chen, FS ;

Yang, DS ;

Petanceska, S ;

Yang, A ;

Tandon, A ;

Yu, G ;

Rozmahel, R ;

Ghiso, J ;

Nishimura, M ;

Zhang, DM ;

Kawara, T ;

Levesque, G ;

Mills, J ;

Levesque, L ;

Song, YQ ;

Rogaeva, E ;

Westaway, D ;

Mount, H ;

Gandy, S ;

St George-Hyslop, P ;

Fraser, PE .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (47) :36794-36802

[8] The Alzheimer's disease β-secretase enzyme, BACE1 [J].

Cole, Sarah L. ;

Vassar, Robert .

MOLECULAR NEURODEGENERATION, 2007, 2 (1)

[9] Aph-1, Pen-2, and nicastrin with presenilin generate an active γ-secretase complex [J].

De Strooper, B .

NEURON, 2003, 38 (01) :9-12

[10] PRODUCTION OF INTRACELLULAR AMYLOID-CONTAINING FRAGMENTS IN HIPPOCAMPAL-NEURONS EXPRESSING HUMAN AMYLOID PRECURSOR PROTEIN AND PROTECTION AGAINST AMYLOIDOGENESIS BY SUBTLE AMINO-ACID SUBSTITUTIONS IN THE RODENT SEQUENCE [J].

DESTROOPER, B ;

SIMONS, M ;

MULTHAUP, G ;

VANLEUVEN, F ;

BEYREUTHER, K ;

DOTTI, CG .

EMBO JOURNAL, 1995, 14 (20) :4932-4938

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