University of Ottawa Brain and Mind Institute, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario K1H 8M5, Canada.
Sci Signal. 2017 Dec 19;10(510):eaan6387. doi: 10.1126/scisignal.aan6387.
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 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 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 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.
亨廷顿病（HD）是一种由亨廷顿蛋白（也称为 Htt）扩张引起的神经退行性疾病，随着年龄的增长会诱导神经元细胞死亡。我们发现，用 CTEP 治疗 12 个月大的有症状杂合子和纯合子亨廷顿敲入小鼠 12 周，CTEP 是代谢型谷氨酸受体 5（mGluR5）的负变构调节剂，可减少亨廷顿蛋白聚集体的大小和数量，减弱半胱天冬酶-3 的活性，并减少脑组织中的神经元凋亡和神经元丢失。CTEP 治疗的小鼠运动和认知功能障碍均得到改善。CTEP 减少亨廷顿蛋白聚集体负担与激酶 GSK3β、转录因子 ZBTB16 和自噬因子 ATG14 介导的自噬途径的激活有关。用 CTEP 抑制 mGluR5 还减少了自噬体生物发生相关激酶 ULK1 的抑制性磷酸化，增加了自噬因子 ATG13 的磷酸化，并增加了同源纯合子小鼠中自噬相关蛋白 Beclin1 的丰度。这些发现表明，mGluR5 拮抗作用可能通过会聚机制激活自噬，促进突变亨廷顿蛋白聚集体的清除，并且可能对 HD 患者具有治疗作用。
