title: PML clastosomes prevent nuclear accumulation of mutant ataxin-7 and other polyglutamine proteins.
abstract: 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, beta-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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale U679, Neurologie et Thérapeutique Expérimentale, 75651 Paris Cedex 13, France. sittler@ccr.jussieu.fr
authors.forename: Alexandre
authors.initials: A
authors.lastname: Janer
authors.forename: Elodie
authors.initials: E
authors.lastname: Martin
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Muriel
authors.forename: Morwena
authors.initials: M
authors.lastname: Latouche
authors.forename: Hiroto
authors.initials: H
authors.lastname: Fujigasaki
authors.forename: Merle
authors.initials: M
authors.lastname: Ruberg
authors.forename: Alexis
authors.initials: A
authors.lastname: Brice
authors.forename: Yvon
authors.initials: Y
authors.lastname: Trottier
authors.forename: Annie
authors.initials: A
authors.lastname: Sittler
mesh_terms: D000818:Animals; D000067719:Ataxin-7; D019556:COS Cells; D019256:Cadmium Chloride / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D009363:Neoplasm Proteins / Q000187:drug effects / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000187:drug effects / Q000378:metabolism*; D010455:Peptides / Q000235:genetics; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D020033:Protein Isoforms / Q000187:drug effects / Q000378:metabolism; D014157:Transcription Factors / Q000187:drug effects / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000187:drug effects / Q000378:metabolism*
chemical_list: C000593829:ATXN7 protein, human; D000067719:Ataxin-7; C000593831:Atxn7 protein, mouse; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C097188:polyglutamine; D016899:Interferon-beta; D046988:Proteasome Endopeptidase Complex; D019256:Cadmium Chloride