Document Detail


A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila.
MedLine Citation:
PMID:  12730384     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The formation of polyglutamine-containing aggregates and inclusions are hallmarks of pathogenesis in Huntington's disease that can be recapitulated in model systems. Although the contribution of inclusions to pathogenesis is unclear, cell-based assays can be used to screen for chemical compounds that affect aggregation and may provide therapeutic benefit. We have developed inducible PC12 cell-culture models to screen for loss of visible aggregates. To test the validity of this approach, compounds that inhibit aggregation in the PC12 cell-based screen were tested in a Drosophila model of polyglutamine-repeat disease. The disruption of aggregation in PC12 cells strongly correlates with suppression of neuronal degeneration in Drosophila. Thus, the engineered PC12 cells coupled with the Drosophila model provide a rapid and effective method to screen and validate compounds.
Authors:
Barbara L Apostol; Alexsey Kazantsev; Simona Raffioni; Katalin Illes; Judit Pallos; Laszlo Bodai; Natalia Slepko; James E Bear; Frank B Gertler; Steven Hersch; David E Housman; J Lawrence Marsh; Leslie Michels Thompson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.     Date:  2003-05-01
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  100     ISSN:  0027-8424     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2003 May 
Date Detail:
Created Date:  2003-05-14     Completed Date:  2003-07-01     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  5950-5     Citation Subset:  IM    
Affiliation:
Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA 92697-4260, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Aggregation
Cell Differentiation
Cell Division
Cell Survival
Cysteine Endopeptidases / metabolism
Disease Models, Animal
Drosophila / genetics*
Exons
Female
Gene Therapy*
Genetic Diseases, Inborn / genetics*,  therapy*
Humans
Multienzyme Complexes / metabolism
Neurites / physiology,  ultrastructure
PC12 Cells
Peptides / antagonists & inhibitors,  genetics*
Phenotype
Proteasome Endopeptidase Complex
Rats
Sequence Deletion
Transfection
Grant Support
ID/Acronym/Agency:
AT00613/AT/NCCAM NIH HHS; CA-62203/CA/NCI NIH HHS; HD36049/HD/NICHD NIH HHS; HD36081/HD/NICHD NIH HHS; NS35255/NS/NINDS NIH HHS; P01HL66105/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Multienzyme Complexes; 0/Peptides; 26700-71-0/polyglutamine; EC 3.4.22.-/Cysteine Endopeptidases; EC 3.4.25.1/Proteasome Endopeptidase Complex
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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