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PMID: 12122205 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

The threshold for polyglutamine-expansion protein aggregation and cellular toxicity is dynamic and influenced by aging in Caenorhabditis elegans.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 99 ·No. 16 ·2002-08-06 ·Pages 10417-22

Morley JF, Brignull HR, Weyers JJ, Morimoto RI

Abstract

Studies of the mutant gene in Huntington's disease, and for eight related neurodegenerative disorders, have identified polyglutamine (polyQ) expansions as a basis for cellular toxicity. This finding has led to a disease hypothesis that protein aggregation and cellular dysfunction can occur at a threshold of approximately 40 glutamine residues. Here, we test this hypothesis by expression of fluorescently tagged polyQ proteins (Q29, Q33, Q35, Q40, and Q44) in the body wall muscle cells of Caenorhabditis elegans and show that young adults exhibit a sharp boundary at 35-40 glutamines associated with the appearance of protein aggregates and loss of motility. Surprisingly, genetically identical animals expressing near-threshold polyQ repeats exhibited a high degree of variation in the appearance of protein aggregates and cellular toxicity that was dependent on repeat length and exacerbated during aging. The role of genetically determined aging pathways in the progression of age-dependent polyQ-mediated aggregation and cellular toxicity was tested by expressing Q82 in the background of age-1 mutant animals that exhibit an extended lifespan. We observed a dramatic delay of polyQ toxicity and appearance of protein aggregates. These data provide experimental support for the threshold hypothesis of polyQ-mediated toxicity in an experimental organism and emphasize the importance of the threshold as a point at which genetic modifiers and aging influence biochemical environment and protein homeostasis in the cell.

MeSH Terms
Aging/metabolism Animals Bacterial Proteins/genetics,metabolism Caenorhabditis elegans/genetics,physiology Luminescent Proteins/genetics,metabolism Peptides/genetics,metabolism Recombinant Fusion Proteins/genetics,metabolism
Chemicals
Bacterial Proteins Luminescent Proteins Peptides Recombinant Fusion Proteins yellow fluorescent protein, Bacteria polyglutamine
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Morley James F
Department of Biochemistry, Molecular Biology, and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA.
Brignull Heather R
Weyers Jill J
Morimoto Richard I
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.152161099
Published
2002-08-06
Epub
2002-00-16
Pages
10417-22
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC124929
Subset
IM
Grants
NIGMS NIH HHS · R37 GM038109 · United States
NIGMS NIH HHS · GM38109 · United States
NIGMS NIH HHS · T32 GM08061 · United States
NIGMS NIH HHS · T32 GM008061 · United States
NIGMS NIH HHS · R01 GM038109 · United States
NIGMS NIH HHS · T32 GM008152 · United States
NIGMS NIH HHS · GM08152 · United States
External Links
PubMed source DOI: 10.1073/pnas.152161099 PMC Full Text View journal details
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