title: Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice.
abstract: 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.
authors.affiliation: 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.
authors.forename: Valeria
authors.initials: V
authors.lastname: Uribe
authors.forename: Bibiana K Y
authors.initials: BK
authors.lastname: Wong
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Corey L
authors.initials: CL
authors.lastname: Cusack
authors.forename: Niels H
authors.initials: NH
authors.lastname: Skotte
authors.forename: Mahmoud A
authors.initials: MA
authors.lastname: Pouladi
authors.forename: Yuanyun
authors.initials: Y
authors.lastname: Xie
authors.forename: Konstantin
authors.initials: K
authors.lastname: Feinberg
authors.forename: Yimiao
authors.initials: Y
authors.lastname: Ou
authors.forename: Yingbin
authors.initials: Y
authors.lastname: Ouyang
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.forename: Sonia
authors.initials: S
authors.lastname: Franciosi
authors.forename: Nagat
authors.initials: N
authors.lastname: Bissada
authors.forename: Amanda
authors.initials: A
authors.lastname: Spreeuw
authors.forename: Weining
authors.initials: W
authors.lastname: Zhang
authors.forename: Dagmar E
authors.initials: DE
authors.lastname: Ehrnhoefer
authors.forename: Kuljeet
authors.initials: K
authors.lastname: Vaid
authors.forename: Freda D
authors.initials: FD
authors.lastname: Miller
authors.forename: Mohanish
authors.initials: M
authors.lastname: Deshmukh
authors.forename: David
authors.initials: D
authors.lastname: Howland
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology; D000544:Alzheimer Disease / Q000201:enzymology / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000201:enzymology / Q000473:pathology; D053178:Caspase 6 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D006801:Humans; D006816:Huntington Disease / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009410:Nerve Degeneration / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009474:Neurons / Q000201:enzymology / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
chemical_list: D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C505516:Casp6 protein, mouse; D053178:Caspase 6