A cell-based assay for aggregation inhibitors as therapeutics of polyglutamine-repeat disease and validation in Drosophila.
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.
Department of Psychiatry and Human Behavior, Gillespie 2121, University of California, Irvine, CA 92697-4260, USA.
Barbara L
BL
Apostol
Alexsey
A
Kazantsev
Simona
S
Raffioni
Katalin
K
Illes
Judit
J
Pallos
Laszlo
L
Bodai
Natalia
N
Slepko
James E
JE
Bear
Frank B
FB
Gertler
Steven
S
Hersch
David E
DE
Housman
J Lawrence
JL
Marsh
Leslie Michels
LM
Thompson
D000818:Animals; D002449:Cell Aggregation; D002454:Cell Differentiation; D002455:Cell Division; D002470:Cell Survival; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics*; D005091:Exons; D005260:Female; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans; D009097:Multienzyme Complexes / Q000378:metabolism; D016501:Neurites / Q000502:physiology / Q000648:ultrastructure; D016716:PC12 Cells; D010455:Peptides / Q000037:antagonists & inhibitors / Q000235:genetics*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex; D051381:Rats; D017384:Sequence Deletion; D014162:Transfection
D009097:Multienzyme Complexes; D010455:Peptides; C097188:polyglutamine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex