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Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice.

  • Uribe, Valeria1
  • Wong, Bibiana K Y
  • Graham, Rona K
  • Cusack, Corey L
  • Skotte, Niels H
  • Pouladi, Mahmoud A
  • Xie, Yuanyun
  • Feinberg, Konstantin
  • Ou, Yimiao
  • Ouyang, Yingbin
  • Deng, Yu
  • Franciosi, Sonia
  • Bissada, Nagat
  • Spreeuw, Amanda
  • Zhang, Weining
  • Ehrnhoefer, Dagmar E
  • Vaid, Kuljeet
  • Miller, Freda D
  • Deshmukh, Mohanish
  • Howland, David
  • And 1 more
  • 1 Department of Medical Genetics, Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia V5Z 4H4, Canada. , (Canada)
Published Article
Human Molecular Genetics
Oxford University Press
Publication Date
May 01, 2012
DOI: 10.1093/hmg/dds005
PMID: 22262731


Apoptosis, or programmed cell death, is a cellular pathway involved in normal cell turnover, developmental tissue remodeling, embryonic development, cellular homeostasis maintenance and chemical-induced cell death. Caspases are a family of intracellular proteases that play a key role in apoptosis. Aberrant activation of caspases has been implicated in human diseases. In particular, numerous findings implicate Caspase-6 (Casp6) in neurodegenerative diseases, including Alzheimer disease (AD) and Huntington disease (HD), highlighting the need for a deeper understanding of Casp6 biology and its role in brain development. The use of targeted caspase-deficient mice has been instrumental for studying the involvement of caspases in apoptosis. The goal of this study was to perform an in-depth neuroanatomical and behavioral characterization of constitutive Casp6-deficient (Casp6-/-) mice in order to understand the physiological function of Casp6 in brain development, structure and function. We demonstrate that Casp6-/- neurons are protected against excitotoxicity, nerve growth factor deprivation and myelin-induced axonal degeneration. Furthermore, Casp6-deficient mice show an age-dependent increase in cortical and striatal volume. In addition, these mice show a hypoactive phenotype and display learning deficits. The age-dependent behavioral and region-specific neuroanatomical changes observed in the Casp6-/- mice suggest that Casp6 deficiency has a more pronounced effect in brain regions that are involved in neurodegenerative diseases, such as the striatum in HD and the cortex in AD.

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