Suppression of mutant huntingtin aggregate formation by Cdk5/p35 through the effect on microtubule stability

Sayuko Kaminosono, Taro Saito, Fumitaka Oyama, Toshio Ohshima, Akiko Asada, Yoshitaka Nagai, Nobuyuki Nukina, Shin Ichi Hisanaga

    Research output: Contribution to journalArticle

    31 Citations (Scopus)

    Abstract

    Huntington's disease (HD) is a polyglutamine [poly(Q)] disease with an expanded poly(Q) stretch in the N terminus of the huntingtin protein (htt). A major pathological feature of HD neurons is inclusion bodies, detergent-insoluble aggregates composed of poly(Q)-expanded mutant htt (mhtt). Misfolding of mhtt is thought to confer a toxic property via formation of aggregates. Although toxic molecular species are still debated, it is important to clarify the aggregation mechanism to understand the pathogenesis of mhtt.Weshow Cdk5/p35 suppresses the formation of mhtt inclusion bodies in cell lines and primary neurons. Although we expressed the N-terminal exon 1 fragment of htt lacking phosphorylation sites for Cdk5 in COS-7 cells, the kinase activity of Cdk5 was required for the suppression. Furthermore, Cdk5/p35 suppressed inclusion formation of atrophin-1, another poly(Q) protein, raising the possibility that Cdk5/p35 generally suppresses inclusion formation of poly(Q) proteins. Microtubules (MTs) were a downstream component of Cdk5/p35 in the suppression of inclusion formation; Cdk5/p35 disrupted MTs, which were required for the formation of inclusions. Moreover, stabilization of MTs by Taxol induced inclusions even with overexpression of Cdk5/p35. The formation of inclusions was also regulated by manipulating the Cdk5/p35 activity in primary rat or mouse cortical neuron cultures. These results indicate that Cdk5-dependent regulation of MT organization is involved in the development of aggregate formation and subsequent pathogenesis of poly(Q) diseases. This Cdk5 inhibition of htt aggregates is a novel mechanism different from htt phosphorylation and interaction with Cdk5 reported previously (Luo et al., 2005; Anne et al., 2007).

    Original languageEnglish
    Pages (from-to)8747-8755
    Number of pages9
    JournalJournal of Neuroscience
    Volume28
    Issue number35
    DOIs
    Publication statusPublished - 2008 Aug 27

    Fingerprint

    Microtubules
    Poisons
    Huntington Disease
    Inclusion Bodies
    Neurons
    Phosphorylation
    COS Cells
    Mutant Proteins
    Paclitaxel
    Detergents
    Exons
    Proteins
    Phosphotransferases
    Huntingtin Protein
    Cell Line

    Keywords

    • Aggregate formation
    • Cdk5/p35
    • Huntingtin
    • Huntington's disease
    • Microtubule
    • Polyglutamine

    ASJC Scopus subject areas

    • Neuroscience(all)
    • Medicine(all)

    Cite this

    Suppression of mutant huntingtin aggregate formation by Cdk5/p35 through the effect on microtubule stability. / Kaminosono, Sayuko; Saito, Taro; Oyama, Fumitaka; Ohshima, Toshio; Asada, Akiko; Nagai, Yoshitaka; Nukina, Nobuyuki; Hisanaga, Shin Ichi.

    In: Journal of Neuroscience, Vol. 28, No. 35, 27.08.2008, p. 8747-8755.

    Research output: Contribution to journalArticle

    Kaminosono, Sayuko ; Saito, Taro ; Oyama, Fumitaka ; Ohshima, Toshio ; Asada, Akiko ; Nagai, Yoshitaka ; Nukina, Nobuyuki ; Hisanaga, Shin Ichi. / Suppression of mutant huntingtin aggregate formation by Cdk5/p35 through the effect on microtubule stability. In: Journal of Neuroscience. 2008 ; Vol. 28, No. 35. pp. 8747-8755.
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    AU - Asada, Akiko

    AU - Nagai, Yoshitaka

    AU - Nukina, Nobuyuki

    AU - Hisanaga, Shin Ichi

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