C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS/FTD

被引：234

作者：

O'Rourke, Jacqueline G. ^{[1
]}

Bogdanik, Laurent ^{[3
]}

Muhammad, A. K. M. G. ^{[1
]}

Gendron, Tania F. ^{[4
]}

Kim, Kevin J. ^{[1
]}

Austin, Andrew ^{[3
]}

Cady, Janet ^{[5
]}

Liu, Elaine Y. ^{[6
]}

Zarrow, Jonah ^{[1
]}

Grant, Sharday ^{[1
]}

Ho, Ritchie ^{[1
]}

Bell, Shaughn ^{[1
]}

Carmona, Sharon ^{[1
]}

Simpkinson, Megan ^{[1
]}

Lall, Deepti ^{[1
]}

Wu, Kathryn ^{[1
]}

Daughrity, Lillian ^{[4
]}

Dickson, Dennis W. ^{[4
]}

Harms, Matthew B. ^{[5
]}

Petrucelli, Leonard ^{[4
]}

Lee, Edward B. ^{[6
]}

Lutz, Cathleen M. ^{[3
]}

Baloh, Robert H. ^{[1
,2
]}

机构：

[1] Cedars Sinai Med Ctr, Board Governors Regenerat Med Inst, Los Angeles, CA 90048 USA

[2] Cedars Sinai Med Ctr, Dept Neurol, Los Angeles, CA 90048 USA

[3] Jackson Lab, Bar Harbor, ME 04609 USA

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

[5] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA

[6] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

来源：

NEURON | 2015年 / 88卷 / 05期

基金：

美国国家卫生研究院;

关键词：

DIPEPTIDE-REPEAT PROTEINS; FRONTOTEMPORAL LOBAR DEGENERATION; AMYOTROPHIC-LATERAL-SCLEROSIS; HEXANUCLEOTIDE REPEAT; RNA FOCI; EXPANDED C9ORF72; GGGGCC REPEAT; EXPANSIONS; TRANSLATION; DEMENTIA;

D O I：

10.1016/j.neuron.2015.10.027

中图分类号：

Q189 [神经科学];

学科分类号：

071006 [神经生物学];

摘要：

Noncoding expansions of a hexanucleotide repeat (GGGGCC) in the C9orf72 gene are the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. Here we report transgenic mice carrying a bacterial artificial chromosome (BAC) containing the full human C9orf72 gene with either a normal allele (15 repeats) or disease-associated expansion (similar to 100-1,000 repeats; C9-BACexp). C9-BACexp mice displayed pathologic features seen in C9orf72 expansion patients, including widespread RNA foci and repeat-associated non-ATG (RAN) translated dipeptides, which were suppressed by antisense oligonucleotides targeting human C9orf72. Nucleolin distribution was altered, supporting that either C9orf72 transcripts or RAN dipeptides promote nucleolar dysfunction. Despite early and widespread production of RNA foci and RAN dipeptides in C9-BACexp mice, behavioral abnormalities and neurodegeneration were not observed even at advanced ages, supporting the hypothesis that RNA foci and RAN dipeptides occur presymptomatically and are not sufficient to drive neurodegeneration in mice at levels seen in patients.

引用

页码：892 / 901

页数：10

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