A progressive translational mouse model of human valosin-containing protein disease: The VCPR155H/+ mouse

Authors

  • Angèle Nalbandian PhD,

    1. Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA
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    • A.N. and K.J.L. are co–first authors of this study.

  • Katrina J. Llewellyn PhD,

    1. Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA
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    • A.N. and K.J.L. are co–first authors of this study.

  • Mallikarjun Badadani PhD,

    1. Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA
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  • Hong Z. Yin MD,

    1. Department of Neurology, University of California, Irvine, Irvine, California, USA
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  • Christopher Nguyen BS,

    1. Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA
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  • Veeral Katheria BS,

    1. Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA
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  • Giles Watts PhD,

    1. Cell Biology and Biochemistry, School of Medicine, Health Policy and Practice, Biomedical Research Centre, University of East Anglia, Norwich, Norfolk, UK
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  • Jogeshwar Mukherjee PhD,

    1. Preclinical Imaging Center, Department of Radiological Sciences, Medical Science C, University of California, Irvine, Irvine, California, USA
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  • Jouni Vesa PhD,

    1. Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA
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  • Vincent Caiozzo PhD,

    1. Department of Orthopedics, University of California, Irvine, Irvine, California, USA
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  • Tahseen Mozaffar MD,

    1. Department of Neurology, University of California, Irvine, Irvine, California, USA
    2. Department of Orthopedics, University of California, Irvine, Irvine, California, USA
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  • John H. Weiss MD, PhD,

    1. Department of Neurology, University of California, Irvine, Irvine, California, USA
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  • Virginia E. Kimonis MD, MRCP

    Corresponding author
    1. Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA
    • Department of Pediatrics, Division of Genetics and Metabolism, 2501 Hewitt Hall, University of California, Irvine, Irvine, California 92696, USA
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Abstract

Introduction:

Mutations in the valosin-containing protein (VCP) gene cause hereditary inclusion body myopathy (IBM) associated with Paget disease of bone (PDB), and frontotemporal dementia (FTD). More recently, these mutations have been linked to 2% of familial amyotrophic lateral sclerosis (ALS) cases. A knock-in mouse model offers the opportunity to study VCP-associated pathogenesis.

Methods:

The VCPR155H/+ knock-in mouse model was assessed for muscle strength and immunohistochemical, Western blot, apoptosis, autophagy, and microPET/CT imaging analyses.

Results:

VCPR155H/+ mice developed significant progressive muscle weakness, and the quadriceps and brain developed progressive cytoplasmic accumulation of TDP-43, ubiquitin-positive inclusion bodies, and increased LC3-II staining. MicroCT analyses revealed Paget-like lesions at the ends of long bones. Spinal cord demonstrated neurodegenerative changes, ubiquitin, and TDP-43 pathology of motor neurons.

Conclusions:

VCPR155H/+ knock-in mice represent an excellent preclinical model for understanding VCP-associated disease mechanisms and future treatments. Muscle Nerve, 2013

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