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

32 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

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)

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