Applying Hsp104 to protein-misfolding disorders.
Applying Hsp104 to protein-misfolding disorders.
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DOI：
10.1139/o09-121
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发表时间：
2010-02
期刊：
影响因子：
--
通讯作者：
Shorter J
中科院分区：
文献类型：
--
作者：
Vashist S;Cushman M;Shorter J
HSP104是一种在酵母中发现的六聚体AAA+ ATPase，将ATP结合和水解的循环转化为解决无序的蛋白质聚集体和交叉β淀粉样蛋白构象体，这些分裂活动通常由HSP70蛋白酶系统进行了相当的选择。第二，淀粉样蛋白通过HSP104的重塑使酵母充分利用了有益的和可遗传的表型变化的储层，尽管在植物，真菌和细菌中，HSP104正交物质实际上是梅物蛋白蛋白酶的，但它是元素的范围。通过将HSP104应用于特定蛋白质不满意的事件是两种致命的神经退行性淀粉样蛋白的可能性，可能会抑制Aβ42淀粉样蛋白发生，这与阿尔茨海默氏病有关关于疾病。通过α-核蛋白在大鼠黑质中的折叠率错过。
Hsp104, a hexameric AAA+ ATPase found in yeast, transduces energy from cycles of ATP binding and hydrolysis to resolve disordered protein aggregates and cross-β amyloid conformers. These disaggregation activities are often co-ordinated by the Hsp70 chaperone system and confer considerable selective advantages. First, renaturation of aggregated conformers by Hsp104 is critical for yeast survival after various environmental stresses. Second, amyloid remodeling by Hsp104 enables yeast to exploit multifarious prions as a reservoir of beneficial and heritable phenotypic variation. Curiously, although highly conserved in plants, fungi and bacteria, Hsp104 orthologues are absent from metazoa. Indeed, metazoan proteostasis seems devoid of a system that couples protein disaggregation to renaturation. Here, we review recent endeavors to enhance metazoan proteostasis by applying Hsp104 to the specific protein-misfolding events that underpin two deadly neurodegenerative amyloidoses. Hsp104 potently inhibits Aβ42 amyloidogenesis, which is connected with Alzheimer's disease, but appears unable to disaggregate preformed Aβ42 fibers. By contrast, Hsp104 inhibits and reverses the formation of α-synuclein oligomers and fibers, which are connected to Parkinson's disease. Importantly, Hsp104 antagonizes the degeneration of dopaminergic neurons induced by α-synuclein misfolding in the rat substantia nigra. These studies raise hopes for developing Hsp104 as a therapeutic agent.
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