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mGluR5 antagonism increases autophagy and prevents disease progression in the zQ175 mouse model of Huntington’s disease
Science Signaling ( IF 7.3 ) Pub Date : 2017-12-19 , DOI: 10.1126/scisignal.aan6387
Khaled S. Abd-Elrahman 1, 2, 3 , Alison Hamilton 1, 2 , Shaunessy R. Hutchinson 1, 2 , Fang Liu 4 , Ryan C. Russell 2 , Stephen S. G. Ferguson 1, 2
Affiliation  

Huntington’s disease (HD) is a neurodegenerative disease caused by an expansion in the huntingtin protein (also called Htt) that induces neuronal cell death with age. We found that the treatment of 12-month-old symptomatic heterozygous and homozygous zQ175 huntingtin knockin mice for 12 weeks with CTEP, a negative allosteric modulator of metabotropic glutamate receptor 5 (mGluR5), reduced the size and number of huntingtin aggregates, attenuated caspase-3 activity, and reduced both neuronal apoptosis and neuronal loss in brain tissue. Both motor and cognitive impairments were improved in CTEP-treated zQ175 mice. The reduction in huntingtin protein aggregate burden by CTEP correlated with the activation of an autophagy pathway mediated by the kinase GSK3β, the transcription factor ZBTB16, and the autophagy factor ATG14. Inhibition of mGluR5 with CTEP also reduced the inhibitory phosphorylation of the autophagosome biogenesis–related kinase ULK1, increased the phosphorylation of the autophagy factor ATG13, and increased the abundance of the autophagy-related protein Beclin1 in homozygous zQ175 mice. The findings suggest that mGluR5 antagonism may activate autophagy through convergent mechanisms to promote the clearance of mutant huntingtin aggregates and might be therapeutic in HD patients.



中文翻译:

mGluR5拮抗作用增加了自噬并阻止了亨廷顿氏病zQ175小鼠模型的疾病进展

亨廷顿舞蹈病(HD)是一种神经退行性疾病,由亨廷顿蛋白(又称Htt)的扩增引起,随着年龄的增长,神经元细胞会死亡。我们发现用CTEP(一种代谢型谷氨酸受体5(mGluR5)的变构调节剂)治疗12个月大的有症状杂合和纯合zQ175亨廷顿敲除小鼠12周,减少了亨廷顿聚集物的大小和数量,减弱了半胱天冬酶- 3活性,并减少脑组织中的神经元凋亡和神经元丢失。CTEP治疗的zQ175可改善运动和认知障碍老鼠。CTEP减少亨廷顿蛋白聚集负担与激活由激酶GSK3β,转录因子ZBTB16和自噬因子ATG14介导的自噬途径有关。用CTEP抑制mGluR5还减少了自噬生物合成相关激酶ULK1的抑制磷酸化,增加了自噬因子ATG13的磷酸化,并增加了自噬相关蛋白Beclin1在纯合zQ175小鼠中的丰度。这些发现表明,mGluR5拮抗作用可能通过收敛机制激活自噬,以促进突变型亨廷顿蛋白聚集物的清除,并且可能对HD患者具有治疗作用。

更新日期:2017-12-20
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