Research ArticleNEURODEGENERATIVE DISEASE

mGluR5 antagonism increases autophagy and prevents disease progression in the zQ175 mouse model of Huntington’s disease

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Sci. Signal.  19 Dec 2017:
Vol. 10, Issue 510, eaan6387
DOI: 10.1126/scisignal.aan6387

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A treatment for Huntington’s disease?

There are currently no therapies that stop or reverse Huntington’s disease (HD), a progressive neurodegenerative disease caused by an expansion in the huntingtin protein that promotes its toxic accumulation in the central nervous system. Impaired autophagy, the process of breaking down and removing cellular debris and dysfunctional proteins, is implicated in HD. Blocking the kinase mTOR therapeutically can activate autophagy, but these drugs have serious side effects and poor penetrance into the brain. Abd-Elrahman et al. found that inhibiting the neuronal cell-surface glutamate receptor mGluR5 with the drug CTEP stimulated autophagy of huntingtin aggregates and improved motor and cognitive performance in HD model mice, without any apparent side effects. Given that CTEP analog is already in clinical trials for other neuronal-associated disorders, these findings suggest that the trials ought to be expanded to include HD patients.

Abstract

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.

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