Abstract
BackgroundHuntington's disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs). Our group has previously demonstrated that calcium (Ca2+) signaling is abnormal in MSNs from the yeast artificial chromosome transgenic mouse model of HD (YAC128). Moreover, we demonstrated that deranged intracellular Ca2+ signaling sensitizes YAC128 MSNs to glutamate-induced excitotoxicity when compared to wild type (WT) MSNs. In previous studies we also observed abnormal neuronal Ca2+ signaling in neurons from spinocerebellar ataxia 2 (SCA2) and spinocerebellar ataxia 3 (SCA3) mouse models and demonstrated that treatment with dantrolene, a ryanodine receptor antagonist and clinically relevant Ca2+ signaling stabilizer, was neuroprotective in experiments with these mouse models. The aim of the current study was to evaluate potential beneficial effects of dantrolene in experiments with YAC128 HD mouse model.ResultsThe application of caffeine and glutamate resulted in increased Ca2+ release from intracellular stores in YAC128 MSN cultures when compared to WT MSN cultures. Pre-treatment with dantrolene protected YAC128 MSNs from glutamate excitotoxicty, with an effective concentration of 100 nM and above. Feeding dantrolene (5 mg/kg) twice a week to YAC128 mice between 2 months and 11.5 months of age resulted in significantly improved performance in the beam-walking and gait-walking assays. Neuropathological analysis revealed that long-term dantrolene feeding to YAC128 mice significantly reduced the loss of NeuN-positive striatal neurons and reduced formation of Httexp nuclear aggregates.ConclusionsOur results support the hypothesis that deranged Ca2+ signaling plays an important role in HD pathology. Our data also implicate the RyanRs as a potential therapeutic target for the treatment of HD and demonstrate that RyanR inhibitors and Ca2+ signaling stabilizers such as dantrolene should be considered as potential therapeutics for the treatment of HD and other polyQ-expansion disorders.
Highlights
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs)
To investigate whether ryanodine receptors (RyanR)-mediated Ca2+-induced Ca2+ release (CICR) can contribute to the total Ca2+ response of YAC128 MSNs to glutamate, we compared Ca2+ responses induced by glutamate, the RyanR agonist caffeine, and the simultaneous application of glutamate and caffeine in wild type (WT) and YAC128 MSNs at 10 days in vitro (DIV)
When cells were treated with glutamate and caffeine together there was a significant increase in the 340/380 nm ratios as compared to glutamate treatment alone in both YAC128 and WT MSNs, suggesting that caffeine treatment can sensitize the intracellular Ca2+ response to glutamate in MSNs (Figure 1C)
Summary
Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a polyglutamine expansion in the Huntingtin protein which results in the selective degeneration of striatal medium spiny neurons (MSNs). Increased Ca2+ influx via extrasynaptic NR2B subunit of N-methyl-D-aspartate receptor (NMDAR) was proposed to play an important role in excitotoxic cell death of HD MSN neurons [4,7,8,9,10,11,12]. These data indicate that Ca2+ signaling plays an important role in the pathogenesis of HD [13,14,15,16]
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