Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans

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 spread...

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Main Authors:	Nussbaum-Krammer, Carmen I., Park, Kyung-Won, Li, Liming, Melki, Ronald, Morimoto, Richard I.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610634/

id	pubmed-3610634
recordtype	oai_dc
spelling	pubmed-36106342013-04-03 Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans Nussbaum-Krammer, Carmen I. Park, Kyung-Won Li, Liming Melki, Ronald Morimoto, Richard I. Research Article 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. Public Library of Science 2013-03-28 /pmc/articles/PMC3610634/ /pubmed/23555277 http://dx.doi.org/10.1371/journal.pgen.1003351 Text en © 2013 Nussbaum-Krammer et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Nussbaum-Krammer, Carmen I. Park, Kyung-Won Li, Liming Melki, Ronald Morimoto, Richard I.
spellingShingle	Nussbaum-Krammer, Carmen I. Park, Kyung-Won Li, Liming Melki, Ronald Morimoto, Richard I. Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans
author_facet	Nussbaum-Krammer, Carmen I. Park, Kyung-Won Li, Liming Melki, Ronald Morimoto, Richard I.
author_sort	Nussbaum-Krammer, Carmen I.
title	Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans
title_short	Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans
title_full	Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans
title_fullStr	Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans
title_full_unstemmed	Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans
title_sort	spreading of a prion domain from cell-to-cell by vesicular transport in caenorhabditis elegans
description	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.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610634/
_version_	1611966022910214144

Spreading of a Prion Domain from Cell-to-Cell by Vesicular Transport in Caenorhabditis elegans

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