 |
|||||
|
|||||
|
|||||
|
|||||
|
|||||
The Journal of Neuroscience, August 27, 2008, 28(35):8747-8755; doi:10.1523/JNEUROSCI.0973-08.2008
Previous Article | Next Article
Neurobiology of Disease
Suppression of Mutant Huntingtin Aggregate Formation by Cdk5/p35 through the Effect on Microtubule Stability
Sayuko Kaminosono,1 * Taro Saito,1 * Fumitaka Oyama,2 Toshio Ohshima,3 Akiko Asada,1 Yoshitaka Nagai,4 Nobuyuki Nukina,2 andShin-ichi Hisanaga1 1Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Tokyo 192-0397, Japan, 2Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Wako, Saitama 351-0198, Japan, 3Department of Life Science and Medical Bio-Science, Waseda University, Tokyo 162-8480, Japan, and 4Division of Clinical Genetics, Department of Medical Genetics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
Correspondence should be addressed to Shin-ichi Hisanaga, Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, 1-1 Minami-osawa, Hachiohji, Tokyo 192-0397, Japan. Email: hisanaga-shinichi{at}tmu.ac.jp
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).
Key words: Huntington's disease; huntingtin; polyglutamine; Cdk5/p35; microtubule; aggregate formation
Received Nov. 14, 2007; revised June 28, 2008; accepted July 21, 2008.
Correspondence should be addressed to Shin-ichi Hisanaga, Department of Biological Sciences, Graduate School of Science, Tokyo Metropolitan University, 1-1 Minami-osawa, Hachiohji, Tokyo 192-0397, Japan. Email: hisanaga-shinichi{at}tmu.ac.jp
This article has been cited by other articles:
M. Pennuto, I. Palazzolo, and A. Poletti
Post-translational modifications of expanded polyglutamine proteins: impact on neurotoxicity
Hum. Mol. Genet., April 15, 2009; 18(R1): R40 - R47.
[Abstract] [Full Text] [PDF]
S. Okada, E. Yamada, T. Saito, K. Ohshima, K. Hashimoto, M. Yamada, Y. Uehara, T. Tsuchiya, H. Shimizu, K. Tatei, et al.
CDK5-dependent Phosphorylation of the Rho Family GTPase TC10{alpha} Regulates Insulin-stimulated GLUT4 Translocation
J. Biol. Chem., December 19, 2008; 283(51): 35455 - 35463.
[Abstract] [Full Text] [PDF]
|
|
|
|
 |
|