title: Spreading of a prion domain from cell-to-cell by vesicular transport in Caenorhabditis elegans.
abstract: Prion proteins can adopt self-propagating alternative conformations that account for the infectious nature of transmissible spongiform encephalopathies (TSEs) and the epigenetic inheritance of certain traits in yeast. Recent evidence suggests a similar propagation of misfolded proteins in the spreading of pathology of neurodegenerative diseases including Alzheimer's or Parkinson's disease. Currently there is only a limited number of animal model systems available to study the mechanisms that underlie the cell-to-cell transmission of aggregation-prone proteins. Here, we have established a new metazoan model in Caenorhabditis elegans expressing the prion domain NM of the cytosolic yeast prion protein Sup35, in which aggregation and toxicity are dependent upon the length of oligopeptide repeats in the glutamine/asparagine (Q/N)-rich N-terminus. NM forms multiple classes of highly toxic aggregate species and co-localizes to autophagy-related vesicles that transport the prion domain from the site of expression to adjacent tissues. This is associated with a profound cell autonomous and cell non-autonomous disruption of mitochondrial integrity, embryonic and larval arrest, developmental delay, widespread tissue defects, and loss of organismal proteostasis. Our results reveal that the Sup35 prion domain exhibits prion-like properties when expressed in the multicellular organism C. elegans and adapts to different requirements for propagation that involve the autophagy-lysosome pathway to transmit cytosolic aggregation-prone proteins between tissues.
authors.affiliation: Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, Illinois, United States of America.
authors.forename: Carmen I
authors.initials: CI
authors.lastname: Nussbaum-Krammer
authors.forename: Kyung-Won
authors.initials: KW
authors.lastname: Park
authors.forename: Liming
authors.initials: L
authors.lastname: Li
authors.forename: Ronald
authors.initials: R
authors.lastname: Melki
authors.forename: Richard I
authors.initials: RI
authors.lastname: Morimoto
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans; D002450:Cell Communication; D004195:Disease Models, Animal; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010454:Peptide Termination Factors / Q000737:chemistry / Q000235:genetics*; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics*; D033921:Vesicular Transport Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D009842:Oligopeptides; D010454:Peptide Termination Factors; D011328:Prions; C068068:SUP35 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D033921:Vesicular Transport Proteins
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