Abstract
Insoluble protein aggregates are consistently found in neurodegenerative disorders caused by expanded polyglutamine [poly(Q)] repeats. The aggregates contain various components of the ubiquitin/proteasome system, suggesting an attempt of the cell to clear the aberrant substrate. To investigate the effect of expanded poly(Q) repeats on ubiquitin/proteasome-dependent proteolysis, we targeted these proteins for proteasomal degradation by the introduction of an N-end rule degradation signal. While soluble poly(Q) proteins were degraded, they resisted proteasomal degradation once present in the aggregates. Stabilization was also observed for proteins that are co-aggregated via interaction with the expanded poly(Q) domain. Introduction of a degradation signal in ataxin-1/Q92 reduced the incidence of nuclear inclusions and the cellular toxicity, conceivably by accelerating the clearance of the soluble substrate.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Ataxin-1
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Ataxins
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Biodegradation, Environmental
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Cysteine Endopeptidases / metabolism*
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Drug Stability
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Green Fluorescent Proteins
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HeLa Cells
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Humans
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Luminescent Proteins / chemistry
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Luminescent Proteins / genetics
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Luminescent Proteins / metabolism
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Macromolecular Substances
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Multienzyme Complexes / metabolism*
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Nerve Tissue Proteins / chemistry
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Nuclear Proteins / chemistry
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Peptides / chemistry*
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Peptides / genetics
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Peptides / metabolism*
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Proteasome Endopeptidase Complex
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Protein Sorting Signals / genetics
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Recombinant Fusion Proteins / chemistry
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Repetitive Sequences, Amino Acid
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Solubility
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Transfection
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Ubiquitin / chemistry
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Ubiquitin / genetics
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Ubiquitin / metabolism
Substances
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ATXN1 protein, human
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Ataxin-1
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Ataxins
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Luminescent Proteins
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Macromolecular Substances
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Multienzyme Complexes
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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Protein Sorting Signals
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Recombinant Fusion Proteins
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Ubiquitin
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Green Fluorescent Proteins
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polyglutamine
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Cysteine Endopeptidases
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Proteasome Endopeptidase Complex