title: Suppression of mutant Huntingtin aggregate formation by Cdk5/p35 through the effect on microtubule stability.
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. We show 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).
authors.affiliation: Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan.
authors.forename: Sayuko
authors.initials: S
authors.lastname: Kaminosono
authors.forename: Taro
authors.initials: T
authors.lastname: Saito
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Oyama
authors.forename: Toshio
authors.initials: T
authors.lastname: Ohshima
authors.forename: Akiko
authors.initials: A
authors.lastname: Asada
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Nukina
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Hisanaga