Metabotropic Glutamate Receptor 5 Antagonism Reduces Pathology and Differentially Improves Symptoms in Male and Female Heterozygous zQ175 Huntington's Mice.

Si Han Li,Stephen S. G. Ferguson,Tash-Lynn L. Colson,Khaled S. Abd-Elrahman

doi:10.3389/fnmol.2022.801757

Si Han Li, Stephen S. G. Ferguson + Show 2 more

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https://doi.org/10.3389/fnmol.2022.801757

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Abstract

Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disorder that leads to progressive motor and cognitive impairment. There are currently no available disease modifying treatments for HD patients. We have previously shown that pharmacological blockade of metabotropic glutamate receptor 5 (mGluR5) signaling rescues motor deficits, improves cognitive impairments and mitigates HD neuropathology in male zQ175 HD mice. Mounting evidence indicates that sex may influence HD progression and we have recently reported a sex-specific pathological mGluR5 signaling in Alzheimer’s disease (AD) mice. Here, we compared the outcomes of treatment with the mGluR5 negative allosteric modulator CTEP (2-chloro-4-[2-[2,5-dimethyl-1-[4-(trifluoromethoxy)phenyl]imidazol-4-yl]ethynyl]pyridine) in both male and female symptomatic zQ175 mice. We found that female zQ175 mice required a longer treatment duration with CTEP than male mice to show improvement in their rotarod performance. Unlike males, chronic CTEP treatment did not improve the grip strength nor reverse the cognitive decline of female zQ175 mice. However, CTEP reduced the number of huntingtin aggregates, improved neuronal survival and decreased microglia activation in the striatum of both male and female zQ175 mice. Together, our results indicate that mGluR5 antagonism can reduce HD neuropathology in both male and female zQ175 HD mice, but sex has a clear impact on the efficacy of the treatment and must be taken into consideration for future HD drug development.

Highlights

Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease characterized by the early loss of medium spiny neurons in the striatum (Martin and Gusella, 1986)
Mutant huntingtin proteins with this expanded polyglutamine repeats have been shown to be targeted for proteolysis and their cleavage at the N-terminus results in the formation of cytoplasmic and intranuclear aggregates that strongly correlate with HD symptoms and severity (DiFiglia et al, 1997)
We have demonstrated that genetic deletion of Metabotropic glutamate receptor 5 (mGluR5) in a Q111 mutant huntingtin knock in mouse model reduces mutant huntingtin aggregate size and improves disease pathology (Ribeiro et al, 2014)

Summary

Introduction

Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease characterized by the early loss of medium spiny neurons in the striatum (Martin and Gusella, 1986). HD is caused by the expansion of a polyglutamine repeat in the N-terminal region of the huntingtin protein (MacDonald et al, 1993). Mutant huntingtin proteins (mHtt) with this expanded polyglutamine repeats have been shown to be targeted for proteolysis and their cleavage at the N-terminus results in the formation of cytoplasmic and intranuclear aggregates that strongly correlate with HD symptoms and severity (DiFiglia et al, 1997). Longer polyglutamine repeats are associated with earlier disease onset and more severe symptoms (Andrew et al, 1993; Furtado et al, 1996). Despite this well-characterized etiology, disease modifying approaches to treat HD are lacking

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