Abstract
Sequence-specific nucleated protein aggregation is closely linked to the pathogenesis of most neurodegenerative diseases and constitutes the molecular basis of prion formation. Here we report that fibrillar polyglutamine peptide aggregates can be internalized by mammalian cells in culture where they gain access to the cytosolic compartment and become co-sequestered in aggresomes together with components of the ubiquitin-proteasome system and cytoplasmic chaperones. Remarkably, these internalized fibrillar aggregates are able to selectively recruit soluble cytoplasmic proteins with which they share homologous but not heterologous amyloidogenic sequences, and to confer a heritable phenotype on cells expressing the homologous amyloidogenic protein from a chromosomal locus.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid / biosynthesis
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Amyloidosis / metabolism*
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Amyloidosis / pathology
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Amyloidosis / physiopathology
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Cell Communication / physiology
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Cell Line
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Cytoplasm / metabolism*
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Cytoplasm / pathology
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Disease Transmission, Infectious
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Endocytosis / physiology*
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Humans
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Huntington Disease / metabolism
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Huntington Disease / physiopathology
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Inclusion Bodies / metabolism*
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Neurodegenerative Diseases / metabolism*
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Neurodegenerative Diseases / pathology
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Neurodegenerative Diseases / physiopathology
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Neurofibrils / metabolism
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Neurofibrils / pathology
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Peptides / metabolism*
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Peptides / toxicity
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Prion Diseases / metabolism
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Prion Diseases / physiopathology
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Proteasome Endopeptidase Complex / metabolism
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Proteasome Endopeptidase Complex / ultrastructure
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Trinucleotide Repeat Expansion / genetics
Substances
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Amyloid
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Peptides
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polyglutamine
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Proteasome Endopeptidase Complex