Tetrabenazine is neuroprotective in Huntington's disease mice

Hongyu Wang, Xi Chen, Yuemei Li, Tie Shan Tang, Ilya Bezprozvanny

Research output: Contribution to journalArticle

53 Scopus citations

Abstract

Background. Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in Huntingtin protein (Htt). PolyQ expansion in Httexp causes selective degeneration of striatal medium spiny neurons (MSN) in HD patients. A number of previous studies suggested that dopamine signaling plays an important role in HD pathogenesis. A specific inhibitor of vesicular monoamine transporter (VMAT2) tetrabenazine (TBZ) has been recently approved by Food and Drug Administration for treatment of HD patients in the USA. TBZ acts by reducing dopaminergic input to the striatum. Results. In previous studies we demonstrated that long-term feeding with TBZ (combined with L-Dopa) alleviated the motor deficits and reduced the striatal neuronal loss in the yeast artificial chromosome transgenic mouse model of HD (YAC128 mice). To further investigate a potential beneficial effects of TBZ for HD treatment, we here repeated TBZ evaluation in YAC128 mice starting TBZ treatment at 2 months of age ("early" TBZ group) and at 6 months of age ("late" TBZ group). In agreement with our previous studies, we found that both "early" and "late" TBZ treatments alleviated motor deficits and reduced striatal cell loss in YAC128 mice. In addition, we have been able to recapitulate and quantify depression-like symptoms in TBZ-treated mice, reminiscent of common side effects observed in HD patients taking TBZ. Conclusions. Our results further support therapeutic value of TBZ for treatment of HD but also highlight the need to develop more specific dopamine antagonists which are less prone to side-effects.

Original languageEnglish (US)
Article number18
JournalMolecular neurodegeneration
Volume5
Issue number1
DOIs
StatePublished - Apr 27 2010

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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