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

Abstract:

: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.

authors

Nollen EA,Garcia SM,van Haaften G,Kim S,Chavez A,Morimoto RI,Plasterk RH

doi

10.1073/pnas.0307697101

keywords:

subject

Has Abstract

pub_date

2004-04-27 00:00:00

pages

6403-8

issue

17

eissn

0027-8424

issn

1091-6490

pii

0307697101

journal_volume

101

pub_type

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