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

Valeria Uribe; Bibiana K Y Wong; Rona K Graham; Corey L Cusack; Niels H Skotte; Mahmoud A Pouladi; Yuanyun Xie; Konstantin Feinberg; Yimiao Ou; Yingbin Ouyang; Yu Deng; Sonia Franciosi; Nagat Bissada; Amanda Spreeuw; Weining Zhang; Dagmar E Ehrnhoefer; Kuljeet Vaid; Freda D Miller; Mohanish Deshmukh; David Howland; Michael R Hayden

doi:10.1093/hmg/dds005

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

Valeria Uribe, Bibiana K Y Wong, Rona K Graham, Corey L Cusack, Niels H Skotte, Mahmoud A Pouladi, Yuanyun Xie, Konstantin Feinberg, Yimiao Ou, Yingbin Ouyang, Yu Deng, Sonia Franciosi, Nagat Bissada, Amanda Spreeuw, Weining Zhang, Dagmar E Ehrnhoefer, Kuljeet Vaid, Freda D Miller, Mohanish Deshmukh, David HowlandMichael R Hayden

50 Citations (Scopus)

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.

Original language	English
Journal	Human Molecular Genetics
Volume	21
Issue number	9
Pages (from-to)	1954-67
Number of pages	14
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/dds005
Publication status	Published - 1 May 2012
Externally published	Yes

Keywords

Aging
Alzheimer Disease
Animals
Apoptosis
Base Sequence
Behavior, Animal
Brain
Caspase 6
Humans
Huntington Disease
Mice
Mice, Knockout
Motor Activity
Nerve Degeneration
Neurons
RNA, Messenger
Receptors, N-Methyl-D-Aspartate

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Uribe, V., Wong, B. K. Y., Graham, R. K., Cusack, C. L., Skotte, N. H., Pouladi, M. A., Xie, Y., Feinberg, K., Ou, Y., Ouyang, Y., Deng, Y., Franciosi, S., Bissada, N., Spreeuw, A., Zhang, W., Ehrnhoefer, D. E., Vaid, K., Miller, F. D., Deshmukh, M., ... Hayden, M. R. (2012). Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice. Human Molecular Genetics, 21(9), 1954-67. https://doi.org/10.1093/hmg/dds005

Uribe, V, Wong, BKY, Graham, RK, Cusack, CL, Skotte, NH, Pouladi, MA, Xie, Y, Feinberg, K, Ou, Y, Ouyang, Y, Deng, Y, Franciosi, S, Bissada, N, Spreeuw, A, Zhang, W, Ehrnhoefer, DE, Vaid, K, Miller, FD, Deshmukh, M, Howland, D & Hayden, MR 2012, 'Rescue from excitotoxicity and axonal degeneration accompanied by age-dependent behavioral and neuroanatomical alterations in caspase-6-deficient mice', Human Molecular Genetics, vol. 21, no. 9, pp. 1954-67. https://doi.org/10.1093/hmg/dds005

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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.",

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AU - Uribe, Valeria

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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

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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 -

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

Abstract

Keywords

UN SDGs

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