title: Cytoplasmic penetration and persistent infection of mammalian cells by polyglutamine aggregates.
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.
authors.affiliation: Department of Biology, Stanford University, Stanford, CA 94305-5020, USA.
authors.forename: Pei-Hsien
authors.initials: PH
authors.lastname: Ren
authors.forename: Jane E
authors.initials: JE
authors.lastname: Lauckner
authors.forename: Ioulia
authors.initials: I
authors.lastname: Kachirskaia
authors.forename: John E
authors.initials: JE
authors.lastname: Heuser
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
authors.forename: Ron R
authors.initials: RR
authors.lastname: Kopito
mesh_terms: D000682:Amyloid / Q000096:biosynthesis; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002450:Cell Communication / Q000502:physiology; D002460:Cell Line; D003593:Cytoplasm / Q000378:metabolism* / Q000473:pathology; D018562:Disease Transmission, Infectious; D004705:Endocytosis / Q000502:physiology*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism / Q000503:physiopathology; D002479:Inclusion Bodies / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009454:Neurofibrils / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000378:metabolism* / Q000633:toxicity; D017096:Prion Diseases / Q000378:metabolism / Q000503:physiopathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000648:ultrastructure; D019680:Trinucleotide Repeat Expansion / Q000235:genetics
chemical_list: D000682:Amyloid; D010455:Peptides; C097188:polyglutamine; D046988:Proteasome Endopeptidase Complex