Abstract
BackgroundHuntington'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.ResultsIn 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.ConclusionsOur 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.
Highlights
Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion in Huntingtin protein (Htt)
TBZ improves motor coordination performance of YAC128 HD mice In the previous study we discovered that long-term oral delivery of TBZ and L-Dopa combination alleviated the motor deficits in aging YAC128 mice [30]
Most of these findings are consistent with an idea that dopamine exerts toxic effects on striatal neurons in the context of HD mutation, which leads in compensatory loss of D1 and D2 receptors in striatal region of HD brains
Summary
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. The cellular mechanisms underlying the cause of MSN neurodegeneration in HD are not very clear, most experimental evidences indicate that polyQ expansion in Httexp leads to a "toxic gain of function" [4]. A number of toxic functions have been assigned to Httexp, such as effects on gene transcription, formation of toxic aggregates, direct induction of apoptosis, disruption of key neuronal functions such as proteosomal or mitochondrial functions, ubiquitination pathways, axonal transport, endocytosis, synaptic transmission and calcium signaling [4,5,6,7,8,9,10,11]. Hyperdopaminergic transmission has been shown to accelerate the formation of Httexp aggregates and promote motor dysfunction in 92Q knock-in HD mouse model
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