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

• Published in: The Journal of cell biology Vol. 174; no. 1; pp. 65 - 76
• Main Authors: Janer, Alexandre, Martin, Elodie, Muriel, Marie-Paule, Latouche, Morwena, Fujigasaki, Hiroto, Ruberg, Merle, Brice, Alexis, Trottier, Yvon, Sittler, Annie
• Format: Journal Article
• Language: English
• Published: United States The Rockefeller University Press 03.07.2006; Rockefeller University Press
• Subjects: Aggregation; Animals; Antibodies; Ataxin-7; Biochemistry, Molecular Biology; Cadmium; Cadmium Chloride; Cadmium Chloride - pharmacology; Cell aggregates; Cell Nucleus; Cell Nucleus - metabolism; Cells; Cells, Cultured; Cercopithecus aethiops; COS Cells; Fluorescent antibody techniques; Humans; Interferon-beta; Interferon-beta - pharmacology; Leukemia; Life Sciences; Mice; Mice, Transgenic; Molecular biology; Multiprotein Complexes; Multiprotein Complexes - drug effects; Multiprotein Complexes - metabolism; Mutation; Neoplasm Proteins; Neoplasm Proteins - drug effects; Neoplasm Proteins - metabolism; Nerve Tissue Proteins; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurological disorders; Neurons; Nuclear Proteins; Nuclear Proteins - drug effects; Nuclear Proteins - metabolism; Peptides; Peptides - genetics; Promyelocytic Leukemia Protein; Proteasome Endopeptidase Complex; Proteasome Endopeptidase Complex - drug effects; Proteasome Endopeptidase Complex - metabolism; Protein Isoforms; Protein Isoforms - drug effects; Protein Isoforms - metabolism; Proteins; Transcription Factors; Transcription Factors - drug effects; Transcription Factors - metabolism; Transfection; Tumor Suppressor Proteins; Tumor Suppressor Proteins - drug effects; Tumor Suppressor Proteins - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200511045

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, β-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.