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Cited by 430Genetic Neurodegenerative DiseasesAmyotrophic Lateral Sclerosis ResearchPrion Diseases and Protein Misfolding

Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease

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Turmaine, Mark, Raza, Aysha, Mahal, Amarbirpal, Mangiarini, Laura, Bates, Gillian P., Davies, Stephen W.·2000·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.110078997PMC PMC16675
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Abstract

Huntington's disease (HD) is a fatal inherited neurodegenerative disorder characterized by personality changes, motor impairment, and subcortical dementia. HD is one of a number of diseases caused by expression of an expanded polyglutamine repeat. We have developed several lines of mice that are transgenic for exon 1 of the HD gene containing an expanded CAG sequence. These mice exhibit a defined neurological phenotype along with neuronal changes that are pathognomonic for the disease. We have previously observed the appearance of neuronal intranuclear inclusions, but did not find evidence for neurodegeneration. In this study, we report that all lines of these mice develop a late onset neurodegeneration within the anterior cingulate cortex, dorsal striatum, and of the Purkinje neurons of the cerebellum. Dying neurons characteristically exhibit neuronal intranuclear inclusions, condensation of both the cytoplasm and nucleus, and ruffling of the plasma membrane while maintaining ultrastructural preservation of cellular organelles. These cells do not develop blebbing of the nucleus or cytoplasm, apoptotic bodies, or fragmentation of DNA. Neuronal death occurs over a period of weeks not hours. We also find degenerating cells of similar appearance within these same regions in brains of patients who had died with HD. We therefore suggest that the mechanism of neuronal cell death in both HD and a transgenic mouse model of HD is neither by apoptosis nor by necrosis.

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  • The R6/2 mouse model is an excellent model to study progressive early synaptic dysfunctions because it mimics the cognitive as well as motor phenotype of HD in the absence of any clear neuronal loss.

    “The HD mouse model, R6/2, is an excellent model to study progressive early synaptic dysfunctions, because this model mimics the cognitive as well as motor phenotype of HD in the absence of any clear neuronal loss.”

    From Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease (2013) · cites this paper as Turmaine et al., 2000

    The Abstract describes a progressive R6/2 neurological phenotype that includes an HD-like movement disorder. It does not establish a cognitive phenotype or examine early synaptic dysfunction. Contrary to an unqualified absence of neuronal loss, the Results report degenerating neurons in R6/2 mice from 14–14.5 weeks of age; page numbers were not supplied. (LLM, conf=0.88)

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  • In R6/2 mice, neuronal loss is not evident until the very end stage of the disease.

    “In R6/2 mice, neuronal loss is not evident until the very end stage of the disease (Turmaine et al., 2000).”

    From Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease (2013) · cites this paper as Turmaine et al., 2000

  • Neuronal loss in R6/2 mice is not evident until the very end stage of the disease.

    “previous studies suggest that neuronal loss in R6/2 mice is not evident until the very end stage of the disease (Turmaine et al., 2000).”

    From Dendritic Spine Instability Leads to Progressive Neocortical Spine Loss in a Mouse Model of Huntington's Disease (2013) · cites this paper as Turmaine et al., 2000

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Cited by

Sorted by citations

Authors
Turmaine, M., Raza, A., Mahal, A., Mangiarini, L., Bates, G. P., & Davies, S. W.
Affiliations
Guy's Hospital (GB)
ORCID
Bates, Gillian P.
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2000-06-27
Volume
97
Issue
14
Pages
8093-8097
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.110078997
PMC
PMC16675
OpenAlex
W1998974178
Cited by
430
References
1
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FWCI
13.32
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
Funders
Wellcome Trust
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
Keywords
Huntington's disease, neuronal cell death, transgenic mouse model, polyglutamine expansion, CAG repeat expansion, neuronal intranuclear inclusions, anterior cingulate cortex, dorsal striatum, Purkinje cells, cerebellum
MeSH terms
Huntingtin Protein, Animals, Cell Nucleus, Cerebellum, Corpus Striatum, Disease Models, Animal, Gyrus Cinguli, Humans, Huntington Disease, Mice, Transgenic, Nerve Tissue Proteins, Neuroglia, Nuclear Proteins, Purkinje Cells, Cell Death, Age of Onset, Trinucleotide Repeat Expansion, In Situ Nick-End Labeling, Mice

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