Compounds blocking mutant huntingtin toxicity identified using a Huntington's disease neuronal cell model

Wenfei Wang, Wenzhen Duan, Shuichi Igarashi, Hokuto Morita, Masayuki Nakamura, Christopher A. Ross

Research output: Contribution to journalArticlepeer-review

Abstract

Neuronal cell death in HD is believed to be largely a dominant cell-autonomous effect of the mutant huntingtin protein. We previously developed an inducible PC12 cell model which expresses an N-terminal huntingtin fragment with an expanded poly Q repeat (N63-148Q) under the control of the tet-off system. In order to evaluate the ability of compounds to protect against mutant huntingtin toxicity in our model, we measured LDH released by dead cells into the medium. We have now screened the library of 1040 compounds from the NINDS Custom Collection as part of a National Institute of Neurological Disorders and Stroke (NINDS) collaborative project. Each positive compound was tested at 3-8 concentrations. Five compounds significantly attenuated mutant huntingtin (htt)-induced LDH release without affecting the expression level of huntingtin and independent of effect on aggregates. We also tested a broad spectrum caspase inhibitor Z-VAD-fmk and previously proposed candidate compounds. This cell model can provide a method to screen potential therapeutic compounds for treating Huntington's disease.

Original languageEnglish (US)
Pages (from-to)500-508
Number of pages9
JournalNeurobiology of Disease
Volume20
Issue number2
DOIs
StatePublished - Nov 1 2005

Keywords

  • Aggregation
  • Cell toxicity
  • Compound screen
  • Huntingtin
  • LDH assay
  • Polyglutamine disease

ASJC Scopus subject areas

  • Neurology

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