Abstract
Expansion of amino acid homo-sequences, such as polyglutamines or polyalanines, in proteins has been directly implicated in various degenerative diseases through a mechanism of protein misfolding and aggregation. However, it is still unclear how the nature of the expansion and the protein context influence the tendency of a protein to aggregate. Here, we have addressed these questions using spinocerebellar ataxia type-3 (ATX3) protein, the best characterised of the polyglutamine proteins, chosen as a model system. Using a transfected mammalian cell line, we demonstrate that ATX3 aggregation is noticeably reduced by deletion or replacement of regions other than the polyglutamine tract. The nature of the amino acid homo-sequences also has a strong influence on aggregation. From our studies, we draw general conclusions on the effect of the protein architecture and of the amino acid homo-sequence on pathology.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acids / physiology*
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Animals
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Ataxin-3
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Biopolymers / chemistry
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COS Cells
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Chlorocebus aethiops
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DNA, Complementary / genetics
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Frameshift Mutation
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Humans
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Machado-Joseph Disease / genetics
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Microscopy, Confocal
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Microscopy, Fluorescence
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Nerve Tissue Proteins / chemistry*
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Nerve Tissue Proteins / deficiency
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / physiology
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Nuclear Proteins / chemistry*
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Nuclear Proteins / deficiency
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Nuclear Proteins / genetics
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Nuclear Proteins / physiology
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Peptides / chemistry*
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Protein Interaction Mapping
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / chemistry
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Repetitive Sequences, Amino Acid*
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Repressor Proteins / chemistry*
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Repressor Proteins / genetics
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Repressor Proteins / physiology
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Sequence Deletion
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Structure-Activity Relationship
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Transfection
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Trinucleotide Repeat Expansion*
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Trinucleotide Repeats*
Substances
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Amino Acids
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Biopolymers
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DNA, Complementary
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Nerve Tissue Proteins
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Nuclear Proteins
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Peptides
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Recombinant Fusion Proteins
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Repressor Proteins
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polyglutamine
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ATXN3 protein, human
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Ataxin-3