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Title
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C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits
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Author
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Abstract
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| 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. |
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Language
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English
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Source (journal)
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Science / American Association for the Advancement of Science [Washington, D.C.] - Washington, D.C., 1880, currens
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Publication
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Washington, D.C.
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American Association for the Advancement of Science
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2015
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ISSN
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0036-8075
[print]
1095-9203
[online]
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DOI
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10.1126/SCIENCE.AAA9344
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Volume/pages
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348
:6239
(2015)
, p. 1151-1154
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ISI
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000355590500052
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Full text (Publisher's DOI)
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