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

TY - JOUR

T1 - Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice

AU - Uribe, Valeria

AU - Wong, Bibiana K Y

AU - Graham, Rona K

AU - Cusack, Corey L

AU - Skotte, Niels H

AU - Pouladi, Mahmoud A

AU - Xie, Yuanyun

AU - Feinberg, Konstantin

AU - Ou, Yimiao

AU - Ouyang, Yingbin

AU - Deng, Yu

AU - Franciosi, Sonia

AU - Bissada, Nagat

AU - Spreeuw, Amanda

AU - Zhang, Weining

AU - Ehrnhoefer, Dagmar E

AU - Vaid, Kuljeet

AU - Miller, Freda D

AU - Deshmukh, Mohanish

AU - Howland, David

AU - Hayden, Michael R

PY - 2012/5/1

Y1 - 2012/5/1

N2 - 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.

AB - 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.

KW - Aging

KW - Alzheimer Disease

KW - Animals

KW - Apoptosis

KW - Base Sequence

KW - Behavior, Animal

KW - Brain

KW - Caspase 6

KW - Humans

KW - Huntington Disease

KW - Mice

KW - Mice, Knockout

KW - Motor Activity

KW - Nerve Degeneration

KW - Neurons

KW - RNA, Messenger

KW - Receptors, N-Methyl-D-Aspartate

U2 - 10.1093/hmg/dds005

DO - 10.1093/hmg/dds005

M3 - Journal article

C2 - 22262731

SN - 0964-6906

VL - 21

SP - 1954

EP - 1967

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 9

ER -