Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease.
Abnormal degradation of the neuronal stress-protective transcription factor HSF1 in Huntington's disease.
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DOI：
10.1038/ncomms14405
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发表时间：
2017-02-13
影响因子：
16.6
通讯作者：
Thiele DJ
中科院分区：
文献类型：
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作者：
Gomez-Pastor R;Burchfiel ET;Neef DW;Jaeger AM;Cabiscol E;McKinstry SU;Doss A;Aballay A;Lo DC;Akimov SS;Ross CA;Eroglu C;Thiele DJ
亨廷顿氏病（HD）是一种神经退行性疾病，由Htt蛋白中的多谷氨酰胺扩增引起，导致Htt错误折叠和细胞死亡。热休克转录因子1 （HSF1）表达的细胞蛋白折叠和促存活机制改善了由蛋白错误折叠引起的生化和神经生物学缺陷。我们报道了HSF1在表达突变Htt的细胞和小鼠、源自人类HD多能干细胞的中棘神经元和HD患者的脑样本中被降解。突变体Htt增加CK2α′激酶和Fbxw7 E3连接酶水平，磷酸化HSF1并促进其蛋白酶体降解。与CK2α′纯合的HD小鼠相比，CK2α′杂合的HD小鼠模型显示HSF1和伴侣水平升高，纹状体兴奋性突触维持，Htt聚集物清除和体重保持。这些结果揭示了一种可以调节的途径，以防止HD中蛋白质错误折叠引起的神经元功能障碍和肌肉萎缩。亨廷顿氏病（HD）是由突变的Htt蛋白错误折叠引起的。作者发现，在HD模型中，通常保护蛋白质错误折叠的热休克转录因子1的表达减少部分是由于CK2α′激酶和Fbxw7 E3连接酶表达升高引起的。
Huntington's Disease (HD) is a neurodegenerative disease caused by poly-glutamine expansion in the Htt protein, resulting in Htt misfolding and cell death. Expression of the cellular protein folding and pro-survival machinery by heat shock transcription factor 1 (HSF1) ameliorates biochemical and neurobiological defects caused by protein misfolding. We report that HSF1 is degraded in cells and mice expressing mutant Htt, in medium spiny neurons derived from human HD iPSCs and in brain samples from patients with HD. Mutant Htt increases CK2α′ kinase and Fbxw7 E3 ligase levels, phosphorylating HSF1 and promoting its proteasomal degradation. An HD mouse model heterozygous for CK2α′ shows increased HSF1 and chaperone levels, maintenance of striatal excitatory synapses, clearance of Htt aggregates and preserves body mass compared with HD mice homozygous for CK2α′. These results reveal a pathway that could be modulated to prevent neuronal dysfunction and muscle wasting caused by protein misfolding in HD. Huntington's disease (HD) is caused by misfolding of mutant Htt protein. The authors find that in HD models, the decreased expression of heat shock transcription factor 1 that usually protects against protein misfolding, is in part caused by elevated CK2α' kinase and Fbxw7 E3 ligase expression.