| Hsp70- and Hsp90-mediated proteasomal degradation underlies TPI sugarkill pathogenesis in Drosophila. | |
| | |
MedLine Citation:
|
PMID: 20727972 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
Triosephosphate isomerase (TPI) deficiency is a severe glycolytic enzymopathy that causes progressive locomotor impairment and neurodegeneration, susceptibility to infection, and premature death. The recessive missense TPI(sugarkill) mutation in Drosophila melanogaster exhibits phenotypes analogous to human TPI deficiency such as progressive locomotor impairment, neurodegeneration, and reduced life span. We have shown that the TPI(sugarkill) protein is an active stable dimer; however, the mutant protein is turned over by the proteasome reducing cellular levels of this glycolytic enzyme. As proteasome function is often coupled with molecular chaperone activity, we hypothesized that TPI(sugarkill) is recognized by molecular chaperones that mediate the proteasomal degradation of the mutant protein. Coimmunoprecipitation data and analyses of TPI(sugarkill) turnover in animals with reduced or enhanced molecular chaperone activity indicate that both Hsp90 and Hsp70 are important for targeting TPI(sugarkill) for degradation. Furthermore, molecular chaperone and proteasome activity modified by pharmacological or genetic manipulations resulted in improved TPI(sugarkill) protein levels and rescue some but not all of the disease phenotypes suggesting that TPI deficiency pathology is complex. Overall, these data demonstrate a surprising role for Hsp70 and Hsp90 in the progression of neural dysfunction associated with TPI deficiency. |
| | |
Authors:
|
Stacy L Hrizo; Michael J Palladino |
Publication Detail:
|
Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-08-19 |
Journal Detail:
|
Title: Neurobiology of disease Volume: 40 ISSN: 1095-953X ISO Abbreviation: Neurobiol. Dis. Publication Date: 2010 Dec |
Date Detail:
|
Created Date: 2010-10-15 Completed Date: 2011-01-25 Revised Date: 2011-12-21 |
Medline Journal Info:
|
Nlm Unique ID: 9500169 Medline TA: Neurobiol Dis Country: United States |
Other Details:
|
Languages: eng Pagination: 676-83 Citation Subset: IM |
Copyright Information:
|
Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
|
Deparment of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
Animals Blotting, Western Drosophila melanogaster HSP70 Heat-Shock Proteins / metabolism* HSP90 Heat-Shock Proteins / metabolism* Immunoprecipitation Motor Activity / genetics Mutation, Missense Proteasome Endopeptidase Complex / metabolism* Triose-Phosphate Isomerase / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
|
R01 AG025046-05/AG/NIA NIH HHS; R01 AG027453-02/AG/NIA NIH HHS; R01AG025046/AG/NIA NIH HHS; R01AG027453/AG/NIA NIH HHS |
| Chemical | |
Reg. No./Substance:
|
0/HSP70 Heat-Shock Proteins; 0/HSP90 Heat-Shock Proteins; EC 3.4.25.1/Proteasome Endopeptidase Complex; EC 5.3.1.1/Triose-Phosphate Isomerase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Reduced gluconeogenesis and lactate clearance in Huntington's disease.
Next Document: Features of bilirubin-induced reactive microglia: from phagocytosis to inflammation.