Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein
Harnessing chaperone-mediated autophagy for the selective degradation of mutant huntingtin protein
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DOI：
10.1038/nbt.1608
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发表时间：
2010-03-01
影响因子：
46.9
通讯作者：
Nukina, Nobuyuki
中科院分区：
文献类型：
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作者：
Bauer, Peter O.;Goswami, Anand;Nukina, Nobuyuki
亨廷顿病（HD）是由含有扩展的多聚谷氨酰胺（polyQ）道的突变亨廷顿蛋白（HTT）的积累引起的显性遗传性病理。由于已知多聚谷氨酰胺结合肽1（QBP 1）结合扩展的polyQ束，但不结合在正常HTT中发现的polyQ基序，因此我们通过在HD的细胞和小鼠模型中表达包含两个拷贝的QBP 1和两个不同的热休克同源蛋白70（HSC 70）结合基序的拷贝的融合分子来选择性地靶向突变HTT用于降解。分子伴侣介导的自噬有助于表达构建体的培养细胞中突变HTT的特异性降解。表达融合分子的病毒的纹状体内递送改善了HD的R6/2小鼠模型中的疾病表型。包含与适当的结构特异性结合剂融合的HSC 70结合基序的类似衔接子分子可能具有治疗由错误折叠的蛋白质引起的疾病的治疗潜力，而不是具有扩展的polyQ束的那些。
Huntington's Disease (HD) is a dominantly inherited pathology caused by the accumulation of mutant huntingtin protein (HTT) containing an expanded polyglutamine (polyQ) tract. As the polyglutamine binding peptide 1 (QBP1) is known to bind an expanded polyQ tract but not the polyQ motif found in normal HTT, we selectively targeted mutant HTT for degradation by expressing a fusion molecule comprising two copies of QBP1 and copies of two different heat shock cognate protein 70 (HSC70)-binding motifs in cellular and mouse models of HD. Chaperone-mediated autophagy contributed to the specific degradation of mutant HTT in cultured cells expressing the construct. Intrastriatal delivery of a virus expressing the fusion molecule ameliorated the disease phenotype in the R6/2 mouse model of HD. Similar adaptor molecules comprising HSC70-binding motifs fused to an appropriate structure-specific binding agent(s) may have therapeutic potential for treating diseases caused by misfolded proteins other than those with expanded polyQ tracts.