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. Author Summary Alzheimer’s, Parkinson’s, Huntington’s, frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and prion diseases are all age-related, fatal neurodegenerative disorders. Hallmarks of these diseases include the expression of toxic protein species. The ability to spread and infect naive cells was thought to be limited to prions but has recently been observed for other disease-linked protein aggregates in tissue culture cells and transgenic mice. The underlying cellular pathways of this cell-to-cell transmission, however, remain elusive. We have developed a new prion model in the roundworm Caenorhabditis elegans and show that the appearance of aggregate species is associated with cellular toxicity, not only in the expressing cell but as well as in adjacent tissues. We monitored in real time the spreading of prion domains by autophagy-derived lysosomal vesicles from cell-to-cell. Given that autophagy and lysosomal degradation have a role in several neurodegenerative diseases, this cellular pathway might be the basis of amyloid infectivity in general.
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