C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits

被引：313

作者：

Chew, Jeannie ^{[1
,2
]}

Gendron, Tania F. ^{[1
]}

Prudencio, Mercedes ^{[1
]}

Sasaguri, Hiroki ^{[1
]}

Zhang, Yong-Jie ^{[1
]}

Castanedes-Casey, Monica ^{[1
]}

Lee, ChrisW. ^{[1
]}

Jansen-West, Karen ^{[1
]}

Kurti, Aishe ^{[1
]}

Murray, Melissa E. ^{[1
]}

Bieniek, Kevin F. ^{[1
,2
]}

Bauer, Peter O. ^{[1
]}

Whitelaw, Ena C. ^{[1
]}

Rousseau, Linda ^{[1
]}

Stankowski, Jeannette N. ^{[1
]}

Stetler, Caroline ^{[1
]}

Daughrity, Lillian M. ^{[1
]}

Perkerson, Emilie A. ^{[1
]}

Desaro, Pamela ^{[3
]}

Johnston, Amelia ^{[3
]}

Overstreet, Karen ^{[3
]}

Edbauer, Dieter ^{[4
,5
,6
]}

Rademakers, Rosa ^{[1
,2
]}

Boylan, Kevin B. ^{[3
]}

Dickson, Dennis W. ^{[1
,2
]}

Fryer, John D. ^{[1
,2
]}

Petrucelli, Leonard ^{[1
,2
]}

机构：

[1] Mayo Clin, Dept Neurosci, Jacksonville, FL 32224 USA

[2] Mayo Clin, Coll Med, Mayo Grad Sch, Neurobiol Dis Grad Program, Rochester, MN 55905 USA

[3] Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA

[4] German Ctr Neurodegenerat Dis DZNE Munich, D-81337 Munich, Germany

[5] Univ Munich, Inst Metab Biochem, D-81337 Munich, Germany

[6] Munich Cluster Syst Neurol SyNergy, Munich, Germany

来源：

SCIENCE | 2015年 / 348卷 / 6239期

基金：

欧洲研究理事会;

关键词：

HEXANUCLEOTIDE REPEAT; RNA FOCI; FRONTOTEMPORAL DEMENTIA; GGGGCC REPEAT; PROTEINS; TRANSLATION; TRANSCRIPTS; INCLUSIONS; TOXICITY; FEATURES;

D O I：

10.1126/science.aaa9344

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The major genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis is a G(4)C(2) repeat expansion in C9ORF72. Efforts to combat neurodegeneration associated with "c9FTD/ALS" are hindered by a lack of animal models recapitulating disease features. We developed a mouse model to mimic both neuropathological and clinical c9FTD/ALS phenotypes. We expressed (G(4)C(2))(66) throughout the murine central nervous system by means of somatic brain transgenesis mediated by adeno-associated virus. Brains of 6-month-old mice contained nuclear RNA foci, inclusions of poly(Gly-Pro), poly(Gly-Ala), and poly(Gly-Arg) dipeptide repeat proteins, as well as TDP-43 pathology. These mouse brains also exhibited cortical neuron and cerebellar Purkinje cell loss, astrogliosis, and decreased weight. (G(4)C(2))(66) mice also developed behavioral abnormalities similar to clinical symptoms of c9FTD/ALS patients, including hyperactivity, anxiety, antisocial behavior, and motor deficits.

引用

页码：1151 / 1154

页数：4

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