Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates

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Abstract
Fibrillar polyglutamine aggregates are taken up by mammalian cells in culture and associate with aggresomes that contain both proteasome subunits and chaperones. Aggresomes also recruit soluble proteins that share the same amyloidogenic sequences as the internalised polyglutamine aggregates. Sequence-specific nucleated protein aggregation is closely linked to the pathogenesis of most neurodegenerative diseases and constitutes the molecular basis of prion formation1. 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.