Original Paper

Acta Neuropathologica

, Volume 125, Issue 2, pp 273-288

Open Access This content is freely available online to anyone, anywhere at any time.

Overexpression of human wild-type FUS causes progressive motor neuron degeneration in an age- and dose-dependent fashion

  • Jacqueline C. MitchellAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration Research
  • , Philip McGoldrickAffiliated withSobell Department of Motor Neuroscience and Movement Disorders, MRC Centre for Neuromuscular Disease, UCL Institute of Neurology
  • , Caroline VanceAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration Research
  • , Tibor HortobagyiAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration Research
  • , Jemeen SreedharanAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration Research
  • , Boris RogeljAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration Research
  • , Elizabeth L. TudorAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration ResearchDepartment of Neuroscience, Institute of Psychiatry
  • , Bradley N. SmithAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration Research
  • , Christian KlasenAffiliated withGenetics of Metabolic and Reproductive Disorders, Max Delbrück Center for Molecular Medicine
    • , Christopher C. J. MillerAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration ResearchDepartment of Neuroscience, Institute of Psychiatry
    • , Jonathan D. CooperAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration Research
    • , Linda GreensmithAffiliated withSobell Department of Motor Neuroscience and Movement Disorders, MRC Centre for Neuromuscular Disease, UCL Institute of Neurology
    • , Christopher E. ShawAffiliated withDepartment of Clinical Neuroscience, Kings College London, King’s Centre for Neurodegeneration Research Email author 

Abstract

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are relentlessly progressive neurodegenerative disorders with overlapping clinical, genetic and pathological features. Cytoplasmic inclusions of fused in sarcoma (FUS) are the hallmark of several forms of FTLD and ALS patients with mutations in the FUS gene. FUS is a multifunctional, predominantly nuclear, DNA and RNA binding protein. Here, we report that transgenic mice overexpressing wild-type human FUS develop an aggressive phenotype with an early onset tremor followed by progressive hind limb paralysis and death by 12 weeks in homozygous animals. Large motor neurons were lost from the spinal cord accompanied by neurophysiological evidence of denervation and focal muscle atrophy. Surviving motor neurons in the spinal cord had greatly increased cytoplasmic expression of FUS, with globular and skein-like FUS-positive and ubiquitin-negative inclusions associated with astroglial and microglial reactivity. Cytoplasmic FUS inclusions were also detected in the brain of transgenic mice without apparent neuronal loss and little astroglial or microglial activation. Hemizygous FUS overexpressing mice showed no evidence of a motor phenotype or pathology. These findings recapitulate several pathological features seen in human ALS and FTLD patients, and suggest that overexpression of wild-type FUS in vulnerable neurons may be one of the root causes of disease. Furthermore, these mice will provide a new model to study disease mechanism, and test therapies.