Howarth Joanna L, Glover Colin P J, Uney James B
University of Bristol, UK.
J Neurochem. 2009 Feb;108(4):945-951. doi: 10.1111/j.1471-4159.2008.05847.x.
Heat shock proteins (HSPs) are associated with the proteinaceous inclusions that characterise many neurodegenerative diseases. This suggests they may be associated with disease aetiology and/or represents an attempt to remove abnormal protein aggregates. In this study the adenoviral mediated over-expression of HSP70 interacting protein (HIP) alone was shown to significantly reduce inclusion formation in both an in vitro model of Spinal Bulbar Muscular Atrophy and a primary neuronal model of polyglutamine disease. Experiments to determine the mechanism of action showed that: denatured luciferase activity (a measure of protein refolding) was not increased in the presence of HIP alone but was increased when HIP was co-expressed with HSP70 or Heat Shock cognate protein 70 (HSC70); the expression of polyglutamine inclusions in cortical neurons mediated an increase in the levels of HSC70 but not HSP70. Our data suggest that HIP may prevent inclusion formation by facilitating the constitutive HSC70 refolding cycle and possibly by preventing aggregation. HIP expression is not increased following stress and its over-expression may therefore reduce toxic polyglutamine aggregation events and contribute to an effective therapeutic strategy.
热休克蛋白（HSPs）与许多神经退行性疾病所特有的蛋白质内含物有关。这表明它们可能与疾病病因相关和/或代表了清除异常蛋白质聚集体的一种尝试。在本研究中，单独腺病毒介导的HSP70相互作用蛋白（HIP）过表达在延髓脊髓性肌萎缩体外模型和多聚谷氨酰胺疾病原代神经元模型中均显示能显著减少内含物形成。确定作用机制的实验表明：单独存在HIP时，变性荧光素酶活性（蛋白质重折叠的一种度量）未增加，但当HIP与HSP70或热休克同源蛋白70（HSC70）共表达时则增加；皮质神经元中多聚谷氨酰胺内含物的表达介导了HSC70水平的增加，但未介导HSP70水平的增加。我们的数据表明，HIP可能通过促进组成型HSC70重折叠循环以及可能通过防止聚集来预防内含物形成。应激后HIP表达未增加，因此其过表达可能减少有毒的多聚谷氨酰胺聚集事件，并有助于形成有效的治疗策略。
