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Cited by 78Cell death mechanisms and regulationAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

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

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Uribe, Valeria, Wong, Bibiana K.Y., Graham, Rona K., Cusack, Corey L., Skotte, Niels H., Pouladi, Mahmoud A., Xie, Yuanyun, Feinberg, Konstantin +13 more·2012·Human Molecular Genetics
DOI 10.1093/hmg/dds005PMC PMC3315204
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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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  • Overexpression of NMNAT1 & 2, which delays axonal disruption propagating from a transaction site, is neuroprotective in tauopathy models.

    “Notably, overexpression of nicotinamide mononucleotide adenylyl transferase 1 & 2 (NMNAT1 & 2), which delays the process of axonal disruption propagating from a transaction site, was found to be neuroprotective in tauopathy models 6465.”

    From Amyloid-beta induced retrograde axonal degeneration in a mouse tauopathy model (2019) · cites this paper as [65]

    The Results and Discussion passages concern protection from axonal degeneration through caspase-6 deficiency, not NMNAT1 or NMNAT2 overexpression. Searches for NMNAT overexpression, tauopathy models, and degeneration from a transection site found no passage addressing the attributed claim. Page numbers were not available in our copy. (LLM, conf=0.75)

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Cited by

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Authors
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., Howland, D., & Hayden, M. R.
Affiliations
  • University of British Columbia (CA)
  • University of North Carolina at Chapel Hill (US)
  • University of Copenhagen (DK)
  • Hospital for Sick Children (CA)
  • University of Toronto (CA)
  • CHDI Foundation (US)
Corresponding author
Hayden, Michael R.
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2012-01-18
Volume
21
Issue
9
Pages
1954-1967
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/dds005
PMC
PMC3315204
OpenAlex
W2139329885
Cited by
78
References
5
Citations by year
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FWCI
4.25
Type
journal article
Language
en
Open access
Locations
  • Human Molecular Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • Pfizer
  • CHDI Foundation
  • British Columbia Innovation Council
  • Michael Smith Health Research BC
  • Austrian Science Fund
  • Consejo Nacional de Ciencia y Tecnología
  • National Institutes of Health
  • Canadian Institutes of Health Research (CIHR MOP-14446, CIHR MOP-84438, MOP-84438, MOP-14446)
  • National Institute of Neurological Disorders and Stroke (NIH NS042197, R01NS042197, T32NS007431)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
caspase-6, excitotoxicity, axonal degeneration, nerve growth factor deprivation, myelin, apoptosis, neurodegeneration, brain development, cortical volume, striatal volume, learning deficits, age-related changes, Alzheimer's disease, Huntington's disease
MeSH terms
Aging, Alzheimer Disease, Animals, Base Sequence, Behavior, Animal, Brain, Humans, Huntington Disease, Motor Activity, Nerve Degeneration, Neurons, RNA, Messenger, Receptors, N-Methyl-D-Aspartate, Apoptosis, Mice, Knockout, Mice, Caspase 6

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