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首页> 外文期刊>Molecular Neurodegeneration >Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model
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Histone deacetylase-3 interacts with ataxin-7 and is altered in a spinocerebellar ataxia type 7 mouse model

机译：组蛋白脱乙酰基酶3与紫杉醇7相互作用，并在脊髓小脑共济失调7型小鼠模型中发生改变。

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Spinocerebellar ataxia type 7 (SCA7) is caused by a toxic polyglutamine (polyQ) expansion in the N-terminus of the protein ataxin-7. Ataxin-7 has a known function in the histone acetylase complex, Spt/Ada/Gcn5 acetylase (STAGA) chromatin-remodeling complex. We hypothesized that some histone deacetylase (HDAC) family members would impact the posttranslational modification of normal and expanded ataxin-7 and possibly modulate ataxin-7 function or neurotoxicity associated with the polyQ expansion. Interestingly, when we coexpressed each HDAC family member in the presence of ataxin-7 we found that HDAC3 increased the posttranslational modification of normal and expanded ataxin-7. Specifically, HDAC3 stabilized ataxin-7 and increased modification of the protein. Further, HDAC3 physically interacts with ataxin-7. The physical interaction of HDAC3 with normal and polyQ-expanded ataxin-7 affects the toxicity in a polyQ-dependent manner. We detect robust HDAC3 expression in neurons and glia in the cerebellum and an increase in the levels of HDAC3 in SCA7 mice. Consistent with this we found altered lysine acetylation levels and deacetylase activity in the brains of SCA7 transgenic mice. This study implicates HDAC3 and ataxin-7 interaction as a target for therapeutic intervention in SCA7, adding to a growing list of neurodegenerative diseases that may be treated by HDAC inhibitors.
机译：脊髓小脑性共济失调7型（SCA7）是由蛋白质紫杉素7的N末端的有毒多聚谷氨酰胺（polyQ）扩展引起的。 Ataxin-7在组蛋白乙酰化酶复合物Spt / Ada / Gcn5乙酰化酶（STAGA）染色质重塑复合物中具有已知功能。我们假设某些组蛋白脱乙酰基酶（HDAC）家族成员会影响正常和扩展的ataxin-7的翻译后修饰，并可能调节与polyQ扩展相关的ataxin-7的功能或神经毒性。有趣的是，当我们在ataxin-7存在下共表达每个HDAC家族成员时，我们发现HDAC3增加了正常和扩展的ataxin-7的翻译后修饰。具体而言，HDAC3稳定了ataxin-7并增加了蛋白质的修饰。此外，HDAC3与紫杉素7物理相互作用。 HDAC3与正常的和polyQ扩展的ataxin-7的物理相互作用以polyQ依赖性方式影响毒性。我们检测到小脑神经元和神经胶质细胞中强健的HDAC3表达，以及SCA7小鼠中HDAC3的水平增加。与此相一致，我们发现SCA7转基因小鼠大脑中的赖氨酸乙酰化水平和脱乙酰酶活性发生了变化。这项研究牵涉到HDAC3和ataxin-7的相互作用作为SCA7治疗干预的靶点，从而增加了越来越多的可由HDAC抑制剂治疗的神经退行性疾病。

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