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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Ataxin-7
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COS Cells
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Cadmium Chloride / pharmacology
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Cell Nucleus / metabolism*
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Cells, Cultured
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Chlorocebus aethiops
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Humans
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Interferon-beta / pharmacology
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Mice
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Mice, Transgenic
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Multiprotein Complexes / drug effects
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Multiprotein Complexes / metabolism*
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Mutation
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Neoplasm Proteins / drug effects
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Neoplasm Proteins / metabolism*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism*
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Nuclear Proteins / drug effects
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Nuclear Proteins / metabolism*
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Peptides / genetics
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Promyelocytic Leukemia Protein
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Proteasome Endopeptidase Complex / drug effects
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Proteasome Endopeptidase Complex / metabolism*
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Protein Isoforms / drug effects
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Protein Isoforms / metabolism
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Transcription Factors / drug effects
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Transcription Factors / metabolism*
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Tumor Suppressor Proteins / drug effects
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Tumor Suppressor Proteins / metabolism*
Substances
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ATXN7 protein, human
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Ataxin-7
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Atxn7 protein, mouse
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Multiprotein Complexes
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Neoplasm Proteins
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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Pml protein, mouse
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Promyelocytic Leukemia Protein
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Protein Isoforms
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Transcription Factors
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Tumor Suppressor Proteins
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PML protein, human
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polyglutamine
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Interferon-beta
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Proteasome Endopeptidase Complex
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Cadmium Chloride