A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration

J. Graeme Hodgson, Nadia Agopyan, Claire Anne Gutekunst, Blair R. Leavitt, Fred Lepiane, Roshni Singaraja, Desmond J. Smith, Nagat Bissada, Krista McCutcheon, Jamal Nasir, Laure Jamot, Li Xiao-Jiang, Mary E. Stevens, Erica Rosemond, John C. Roder, Anthony G. Phillips, Edward M. Rubin, Steven M. Hersch, Michael R. Hayden

    Research output: Contribution to journalArticleResearchpeer-review

    Abstract

    We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.
    Original languageEnglish
    Pages (from-to)181-192
    Number of pages12
    JournalNeuron
    Volume23
    DOIs
    Publication statusPublished - 1999

    Fingerprint

    Yeast Artificial Chromosomes
    Corpus Striatum
    Huntington Disease
    Intranuclear Inclusion Bodies
    Transgenic Mice
    Neurons

    Cite this

    Hodgson, J. G., Agopyan, N., Gutekunst, C. A., Leavitt, B. R., Lepiane, F., Singaraja, R., ... Hayden, M. R. (1999). A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. Neuron, 23, 181-192. https://doi.org/10.1016/S0896-6273(00)80764-3
    Hodgson, J. Graeme ; Agopyan, Nadia ; Gutekunst, Claire Anne ; Leavitt, Blair R. ; Lepiane, Fred ; Singaraja, Roshni ; Smith, Desmond J. ; Bissada, Nagat ; McCutcheon, Krista ; Nasir, Jamal ; Jamot, Laure ; Xiao-Jiang, Li ; Stevens, Mary E. ; Rosemond, Erica ; Roder, John C. ; Phillips, Anthony G. ; Rubin, Edward M. ; Hersch, Steven M. ; Hayden, Michael R. / A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. In: Neuron. 1999 ; Vol. 23. pp. 181-192.
    @article{fb71319503af48f4a85e5f24cba2fde0,
    title = "A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration",
    abstract = "We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.",
    author = "Hodgson, {J. Graeme} and Nadia Agopyan and Gutekunst, {Claire Anne} and Leavitt, {Blair R.} and Fred Lepiane and Roshni Singaraja and Smith, {Desmond J.} and Nagat Bissada and Krista McCutcheon and Jamal Nasir and Laure Jamot and Li Xiao-Jiang and Stevens, {Mary E.} and Erica Rosemond and Roder, {John C.} and Phillips, {Anthony G.} and Rubin, {Edward M.} and Hersch, {Steven M.} and Hayden, {Michael R.}",
    year = "1999",
    doi = "10.1016/S0896-6273(00)80764-3",
    language = "English",
    volume = "23",
    pages = "181--192",
    journal = "Neuron",

    }

    Hodgson, JG, Agopyan, N, Gutekunst, CA, Leavitt, BR, Lepiane, F, Singaraja, R, Smith, DJ, Bissada, N, McCutcheon, K, Nasir, J, Jamot, L, Xiao-Jiang, L, Stevens, ME, Rosemond, E, Roder, JC, Phillips, AG, Rubin, EM, Hersch, SM & Hayden, MR 1999, 'A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration', Neuron, vol. 23, pp. 181-192. https://doi.org/10.1016/S0896-6273(00)80764-3

    A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration. / Hodgson, J. Graeme; Agopyan, Nadia; Gutekunst, Claire Anne; Leavitt, Blair R.; Lepiane, Fred; Singaraja, Roshni; Smith, Desmond J.; Bissada, Nagat; McCutcheon, Krista; Nasir, Jamal; Jamot, Laure; Xiao-Jiang, Li; Stevens, Mary E.; Rosemond, Erica; Roder, John C.; Phillips, Anthony G.; Rubin, Edward M.; Hersch, Steven M.; Hayden, Michael R.

    In: Neuron, Vol. 23, 1999, p. 181-192.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - A YAC mouse model for Huntington's disease with full-length mutant huntingtin, cytoplasmic toxicity, and selective striatal neurodegeneration

    AU - Hodgson, J. Graeme

    AU - Agopyan, Nadia

    AU - Gutekunst, Claire Anne

    AU - Leavitt, Blair R.

    AU - Lepiane, Fred

    AU - Singaraja, Roshni

    AU - Smith, Desmond J.

    AU - Bissada, Nagat

    AU - McCutcheon, Krista

    AU - Nasir, Jamal

    AU - Jamot, Laure

    AU - Xiao-Jiang, Li

    AU - Stevens, Mary E.

    AU - Rosemond, Erica

    AU - Roder, John C.

    AU - Phillips, Anthony G.

    AU - Rubin, Edward M.

    AU - Hersch, Steven M.

    AU - Hayden, Michael R.

    PY - 1999

    Y1 - 1999

    N2 - We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.

    AB - We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) huntingtin (htt) in a developmental and tissue-specific manner identical to that observed in Huntington's disease (HD). YAC46 and YAC72 mice show early electrophysiological abnormalities, indicating cytoplasmic dysfunction prior to observed nuclear inclusions or neurodegeneration. By 12 months of age, YAC72 mice have a selective degeneration of medium spiny neurons in the lateral striatum associated with the translocation of N-terminal htt fragments to the nucleus. Neurodegeneration can be present in the absence of macro- or microaggregates, clearly showing that aggregates are not essential to initiation of neuronal death. These mice demonstrate that initial neuronal cytoplasmic toxicity is followed by cleavage of htt, nuclear translocation of htt N-terminal fragments, and selective neurodegeneration.

    UR - https://www.cell.com/neuron/pdf/S0896-6273(00)80764-3.pdf

    UR - http://www.mendeley.com/research/yac-mouse-model-huntingtons-disease-fulllength-mutant-huntingtin-cytoplasmic-toxicity-selective-stri

    U2 - 10.1016/S0896-6273(00)80764-3

    DO - 10.1016/S0896-6273(00)80764-3

    M3 - Article

    VL - 23

    SP - 181

    EP - 192

    JO - Neuron

    JF - Neuron

    ER -