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Published 3 July 2006. doi:10.1083/jcb.200511045
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 174, Number 1, 65-76
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Article

PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins



Alexandre Janer1,2,3, Elodie Martin1,2,3, Marie-Paule Muriel1,2,3, Morwena Latouche1,2,3, Hiroto Fujigasaki6, Merle Ruberg1,2,3, Alexis Brice1,2,3,4, Yvon Trottier5, and Annie Sittler1,2,3

1 Institut National de la Santé et de la Recherche Médicale U679, Neurologie et Thérapeutique Expérimentale, 75651 Paris Cedex 13, France
2 Hôpital de la Pitié-Salpêtrière, 75651 Paris Cedex 13, France
3 Faculté de Médecine, Université Pierre et Marie Curie, 75651 Paris Cedex 13, France
4 Département de Génétique, Cytogénétique et Embryologie, Groupe Hospitalier Pitié-Salpêtrière, 75651 Paris Cedex 13, France
5 Département de Pathologie Moléculaire, Institut de Génétique et Biologie Moléculaire et Cellulaire, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Université Louis Pasteur, BP 10142, Illkirch Cedex, CU de Strasbourg, France
6 Department of Neurology, Musashino Red Cross Hospital, Tokyo 108-8339, Japan

Correspondence to Annie Sittler: sittler{at}ccr.jussieu.fr

The pathogenesis of spinocerebellar ataxia type 7 and other neurodegenerative polyglutamine (polyQ) disorders correlates with the aberrant accumulation of toxic polyQ-expanded proteins in the nucleus. Promyelocytic leukemia protein (PML) nuclear bodies are often present in polyQ aggregates, but their relation to pathogenesis is unclear. We show that expression of PML isoform IV leads to the formation of distinct nuclear bodies enriched in components of the ubiquitin-proteasome system. These bodies recruit soluble mutant ataxin-7 and promote its degradation by proteasome-dependent proteolysis, thus preventing the aggregate formation. Inversely, disruption of the endogenous nuclear bodies with cadmium increases the nuclear accumulation and aggregation of mutant ataxin-7, demonstrating their role in ataxin-7 turnover. Interestingly, ß-interferon treatment, which induces the expression of endogenous PML IV, prevents the accumulation of transiently expressed mutant ataxin-7 without affecting the level of the endogenous wild-type protein. Therefore, clastosomes represent a potential therapeutic target for preventing polyQ disorders.

Abbreviations used in this paper: FMRP, fragile X mental retardation protein; INF, interferon; NI, nuclear inclusion; PML, promyelocytic leukemia protein; polyQ, polyglutamine; SCA7, spinocerebellar ataxia 7; UPS, ubiquitin-proteasome system.


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