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首页> 外文期刊>Molecular and Cellular Biology >Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease
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Regulation of Feedback between Protein Kinase A and the Proteasome System Worsens Huntington's Disease

机译：蛋白激酶A和蛋白酶体系统之间的反馈调节恶化亨廷顿氏病

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Huntington's disease (HD) is a neurodegenerative disease caused by the expansion of a CAG repeat in the Huntingtin (HTT) gene. Abnormal regulation of the cyclic AMP (cAMP)/protein kinase A (PKA) pathway occurs during HD progression. Here we found that lower PKA activity was associated with proteasome impairment in the striatum for two HD mouse models (R6/2 and N171-82Q) and in mutant HTT (mHTT)-expressing striatal cells. Because PKA regulatory subunits (PKA-Rs) are proteasome substrates, the mHTT-evoked proteasome impairment caused accumulation of PKA-Rs and subsequently inhibited PKA activity. Conversely, activation of PKA enhanced the phosphorylation of Rpt6 (a component of the proteasome), rescued the impaired proteasome activity, and reduced mHTT aggregates. The dominant-negative Rpt6 mutant (Rpt6S120A) blocked the ability of a cAMP-elevating reagent to enhance proteasome activity, whereas the phosphomimetic Rpt6 mutant (Rpt6S120D) increased proteasome activity, reduced HTT aggregates, and ameliorated motor impairment. Collectively, our data demonstrated that positive feedback regulation between PKA and the proteasome is critical for HD pathogenesis.
机译：亨廷顿舞蹈病（HD）是由Huntingtin（ HTT ）基因中CAG重复序列的扩增引起的神经退行性疾病。 HD进展过程中发生环状AMP（cAMP）/蛋白激酶A（PKA）途径的异常调节。在这里，我们发现对于两种HD小鼠模型（R6 / 2和N171-82Q）和表达突变型HTT（mHTT）的纹状体细胞，纹状体中PKA活性降低与蛋白酶体损伤有关。由于PKA调节亚基（PKA-Rs）是蛋白酶体的底物，因此mHTT引起的蛋白酶体损伤导致PKA-Rs的积累，进而抑制了PKA的活性。相反，PKA的激活增强了Rpt6（蛋白酶体的一个组成部分）的磷酸化，挽救了受损的蛋白酶体活性，并减少了mHTT聚集体。显性负性Rpt6突变体（Rpt6 S120A ）阻止了cAMP升高试剂增强蛋白酶体活性的能力，而拟磷酸Rpt6突变体（Rpt6 S120D ）增加了蛋白酶体活性。 ，减少了HTT总量并改善了运动障碍。总的来说，我们的数据表明，PKA和蛋白酶体之间的正反馈调节对于HD发病机制至关重要。

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