Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism
Blocking acid-sensing ion channel 1 alleviates Huntington's disease pathology via an ubiquitin-proteasome system-dependent mechanism
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DOI：
10.1093/hmg/ddn218
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发表时间：
2008-10-15
影响因子：
3.5
通讯作者：
Nukina, Nobuyuki
中科院分区：
文献类型：
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作者：
Wong, Hon Kit;Bauer, Peter O.;Nukina, Nobuyuki
亨廷顿病（HD）是一种致命的神经退行性疾病。尽管在几种HD模型中开发治疗工具付出了巨大努力，但目前还没有有效的治愈方法。先前已在细胞和体内模型以及HD患者的脑中观察到酸中毒。在这里，我们挑战HD模型与阿米洛利（Ami）衍生物苯扎米尔（Ben），用于拯救酸敏感离子通道（ASIC）依赖性酸中毒的化学试剂，以检查慢性酸中毒是否是HD病理机制的重要组成部分，以及这些药物是否可以用作新的治疗药物。Ben显著降低了诱导细胞系统中的亨廷顿蛋白-聚谷氨酰胺（htt-polyQ）聚集，并且Ben的治疗价值在HD的R6/2动物模型中成功地再现。为了揭示作用机制，发现Ben能够减轻泛素-蛋白酶体系统（UPS）活性的抑制，导致可溶性htt-polyQ的降解增强，特别是在其病理范围内。更重要的是，我们能够证明，阻断ASIC的一种特定亚型（asic 1a）（Ben的许多分子靶点之一）的表达，导致UPS活性增强，这种阻断也降低了R6/2小鼠纹状体中的ht-polyQ聚集。总之，我们认为，靶向ASIC 1a的化合物或UPS抑制的药理学缓解将是对抗HD和其他polyQ相关疾病的有效且有前景的方法。
Huntington's disease (HD) is a fatal neurodegenerative disorder. Despite a tremendous effort to develop therapeutic tools in several HD models, there is no effective cure at present. Acidosis has been observed previously in cellular and in in vivo models as well as in the brains of HD patients. Here we challenged HD models with amiloride (Ami) derivative benzamil (Ben), a chemical agent used to rescue acid-sensing ion channel (ASIC)-dependent acidotoxicity, to examine whether chronic acidosis is an important part of the HD pathomechanism and whether these drugs could be used as novel therapeutic agents. Ben markedly reduced the huntingtin-polyglutamine (htt-polyQ) aggregation in an inducible cellular system, and the therapeutic value of Ben was successfully recapitulated in the R6/2 animal model of HD. To reveal the mechanism of action, Ben was found to be able to alleviate the inhibition of the ubiquitin-proteasome system (UPS) activity, resulting in enhanced degradation of soluble htt-polyQ specifically in its pathological range. More importantly, we were able to demonstrate that blocking the expression of a specific isoform of ASIC (asic1a), one of the many molecular targets of Ben, led to an enhancement of UPS activity and this blockade also decreased htt-polyQ aggregation in the striatum of R6/2 mice. In conclusion, we believe that chemical compounds that target ASIC1a or pharmacological alleviation of UPS inhibition would be an effective and promising approach to combat HD and other polyQ-related disorders.