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Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation

Nollen, E. A. A., Garcia, S. M., van Haaften, G., Kim, S., Chavez, A., Morimoto, R. I. & Plasterk, R. H. A., 27-Apr-2004, In : Proceedings of the National Academy of Sciences of the United States of America. 101, 17, p. 6403-6408 6 p.

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DOI

  • Ellen A A Nollen
  • Susana M Garcia
  • Gijs van Haaften
  • Soojin Kim
  • Alejandro Chavez
  • Richard I Morimoto
  • Ronald H A Plasterk

Protein misfolding and the formation of aggregates are increasingly recognized components of the pathology of human genetic disease and hallmarks of many neurodegenerative disorders. As exemplified by polyglutamine diseases, the propensity for protein misfolding is associated with the length of polyglutamine expansions and age-dependent changes in protein-folding homeostasis, suggesting a critical role for a protein homeostatic buffer. To identify the complement of protein factors that protects cells against the formation of protein aggregates, we tested transgenic Caenorhabditis elegans strains expressing polyglutamine expansion yellow fluorescent protein fusion proteins at the threshold length associated with the age-dependent appearance of protein aggregation. We used genome-wide RNA interference to identify genes that, when suppressed, resulted in the premature appearance of protein aggregates. Our screen identified 186 genes corresponding to five principal classes of polyglutamine regulators: genes involved in RNA metabolism, protein synthesis, protein folding, and protein degradation; and those involved in protein trafficking. We propose that each of these classes represents a molecular machine collectively comprising the protein homeostatic buffer that responds to the expression of damaged proteins to prevent their misfolding and aggregation.

Original languageEnglish
Pages (from-to)6403-6408
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number17
Publication statusPublished - 27-Apr-2004
Externally publishedYes

    Keywords

  • Animals, Blotting, Western, Caenorhabditis elegans, Genome, Microscopy, Electron, Peptides, RNA Interference, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.

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