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).
