期刊
HUMAN MOLECULAR GENETICS
卷 21, 期 9, 页码 1954-1967出版社
OXFORD UNIV PRESS
DOI: 10.1093/hmg/dds005
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资金
- Canadian Institutes of Health Research (CIHR) [MOP-84438, MOP-14446]
- CHDI Foundation, Inc.
- National Institute of Health (NIH) [NS042197]
- Ripples of Hope Pfizer
- BC Innovation Council Ripples of Hope
- Consejo Nacional de Ciencia y Teconolgia (CONACYT)
- University of North Carolina [T32-NS007431]
- PhD School for Genetic Medicine, University of Copenhagen
- Michael Smith Foundation for Health Research (MSFHR)
- Austrian Science Fund (FWF) [J2797-B09]
- EMBO
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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