Cited by 298Amyotrophic Lateral Sclerosis ResearchGenetic Neurodegenerative DiseasesHereditary Neurological Disorders

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

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O’Rourke, Jacqueline G., Bogdanik, Laurent, Muhammad, A.K.M.G., Gendron, Tania F., Kim, Kevin J., Austin, Andrew, Cady, Janet, Liu, Elaine Y. +15 more·2015·Neuron

Abstract

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 (∼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.

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Crossref · 10.1016/j.neuron.2015.10.027

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  • Deletion of the mouse C9orf72 ortholog leads to splenomegaly, lymphadenopathy, dysregulation of macrophages and microglia, and excess production of inflammatory cytokines.

    “In contrast, deletion of the mouse C9orf72 ortholog leads to splenomegaly, lymphadenopathy, dysregulation of macrophages and microglia, and excess production of inflammatory cytokines [184–187].”

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Authors
O’Rourke, J. G., Bogdanik, L., Muhammad, A. K. M. G., Gendron, T. F., Kim, K. J., Austin, A., Cady, J., Liu, E. Y., Zarrow, J., Grant, S., Ho, R., Bell, S., Carmona, S., Simpkinson, M., Lall, D., Wu, K., Daughrity, L., Dickson, D. W., Harms, M. B., Petrucelli, L., Lee, E. B., Lutz, C. M., & Baloh, R. H.
Affiliations
  • Cedars-Sinai Medical Center (US)
  • Jackson Laboratory (US)
  • Mayo Clinic (US)
  • Washington University in St. Louis (US)
  • University of Pennsylvania (US)
Corresponding author
Baloh, Robert H.
Venue
Neuron
Publisher
Elsevier BV
Published
2015-12
Volume
88
Issue
5
Pages
892-901
ISSN
0896-6273 (ISSN-L)
OpenAlex
W2187620259
Cited by
298
References
41
Citations by year
2026: 6 · 2025: 15 · 2024: 23 · 2023: 12 · 2022: 22 · 2021: 42 · 2020: 36 · 2019: 27 · 2018: 41 · 2017: 31 · 2016: 40 · 2015: 2 · 2014: 1
FWCI
26.79
Type
journal article
Language
en
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Mouseion at the JAXlibrary (Jackson Laboratory) (submittedVersion)
Funders
  • National Institutes of Health (NS055980, NS069669, AG039510, AG000255, NS089979, NS084528, NS063964, NS077402, NS084974, ES20395)
  • Department of Defense ALSRP (AL130125)
  • Mayo Clinic Foundation
  • Mayo Clinic Center for Individualized Medicine
  • ALS Association
  • Robert Packard Center for ALS Research at Johns Hopkins
  • Target ALS
  • Robert and Louise Schwab Family
  • Cedars-Sinai ALS Research Fund
  • National Center for Advancing Translational Sciences (UL1TR000124)
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
Keywords
C9orf72, hexanucleotide repeat expansion, amyotrophic lateral sclerosis, frontotemporal dementia, RNA foci, antisense oligonucleotides, nucleolin, neurodegeneration
MeSH terms
C9orf72 Protein, Age Factors, Amyotrophic Lateral Sclerosis, Animals, Brain, Cells, Cultured, Disease Models, Animal, Humans, Mice, Transgenic, Motor Activity, Neuromuscular Junction, Neurons, Proteins, Psychomotor Performance, Spinal Cord, Glutamic Acid, Chromosomes, Artificial, Bacterial, DNA Repeat Expansion, Mice, Muscle Strength, Frontotemporal Dementia

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