Normalizing glucocorticoid levels attenuates metabolic and neuropathological symptoms in the R6/2 mouse model of huntington's disease

Brett D Dufour,Jodi L Mcbride

doi:10.1016/j.nbd.2018.09.025

Abstract

Huntington's disease (HD) is a fatal genetic neurological disorder caused by a mutation in the human Huntingtin (HTT) gene. This mutation confers a toxic gain of function of the encoded mutant huntingtin (mHTT) protein, leading to widespread neuropathology including the formation of mHTT-positive inclusion bodies, gene dysregulation, reduced levels of adult dentate gyrus neurogenesis and neuron loss throughout many regions of the brain. Additionally, because HTT is ubiquitously expressed, several peripheral tissues are also affected. HD patients suffer from progressive motor, cognitive, psychiatric, and metabolic symptoms, including weight loss and skeletal muscle wasting. HD patients also show neuroendocrine changes including a robust, significant elevation in circulating levels of the glucocorticoid, cortisol. Previously, we confirmed that the R6/2 mouse model of HD exhibits elevated corticosterone (the rodent homolog of cortisol) levels and demonstrated that experimentally elevated corticosterone exacerbates R6/2 HD symptomology, resulting in severe and rapid weight loss and a shorter latency to death. Given that efficacious therapeutics are lacking for HD, here we investigated whether normalizing glucocorticoid levels could serve as a viable therapeutic approach for this disease. We tested the hypothesis that normalizing glucocorticoids to wild-type levels would ameliorate HD symptomology. Wild-type (WT) and transgenic R6/2 mice were allocated to three treatment groups: 1) adrenalectomy with normalized, WT-level corticosterone replacement (10 μg/ml), 2) adrenalectomy with high HD-level corticosterone replacement (35 μg/ml), or 3) sham surgery with no corticosterone replacement. Normalizing corticosterone to WT levels led to an improvement in metabolic rate in male R6/2 mice, as indicated by indirect calorimetry, including a reduction in oxygen consumption and normalization of respiratory exchange ratio values (p < .05 for both). Normalizing corticosterone also ameliorated brain atrophy in female R6/2 mice and skeletal muscle wasting in both male and female R6/2 mice (p < .05 for all). Female R6/2 mice given WT-level corticosterone replacement also showed a reduction in HD neuropathological markers, including a reduction in mHTT inclusion burden in the striatum, cortex, and hippocampus (p < .05 for all). This data illustrates that ameliorating glucocorticoid dysregulation leads to a significant improvement in HD symptomology in the R6/2 mouse model and suggests that cortisol-reducing therapeutics may be of value in improving HD patient quality of life.

Highlights

Huntington’s disease (HD) is a fatal genetic neurodegenerative disorder caused by a CAG triplet repeat expansion in the human huntingtin (HTT) gene (Huntington Disease Collaborative Research Group, 1993)
Given that there are no current FDA-approved medications that can slow the progression of HD symptoms, we investigated whether glucocorticoid dysregulation in HD could serve as a novel point of therapeutic intervention to alleviate HD symptomology
In order to assess the role of glucocorticoids in HD metabolic symptomology and neuropathology, WT and R6/2 HD mice were adrenalectomized at 6 weeks of age and treated with either low dose (10μg/ml, WT level, n=20 HD and n=25 WT) or high dose (35μg/ml, HD level, n=17 per genotype) corticosterone replacement, provided in their drinking water (See Fig. 1A for experimental timeline)

Summary

Introduction

Huntington’s disease (HD) is a fatal genetic neurodegenerative disorder caused by a CAG triplet repeat expansion in the human huntingtin (HTT) gene (Huntington Disease Collaborative Research Group, 1993). If sufficiently long (40+ repeats), this mutation confers a toxic gain of function on the encoded mutant huntingtin protein (mHTT), leading to widespread neuropathology, including robust transcriptional abnormalities, the formation of mHTT+ inclusion bodies, regional reductions in brain volume, altered neurogenesis and neuroinflammation (astrogliosis and microgliosis) (Hodges et al, 2006; Huntington Disease Collaborative Research Group, 1993; Ross et al, 2014; Rub et al, 2015; Sapp et al, 2001; Vonsattel et al, 1985). The hallmark symptom of the disease is chorea, whereby patients show uncontrollable hyperkinetic movements that become progressively more severe (Huntington Study Group, 1996; Ross et al, 2014). HD is typically conceptualized as a movement disorder, patients suffer from severe cognitive, psychiatric, and metabolic symptoms (Anderson and Marder, 2001; Bamford et al, 1995; Kirkwood et al, 2001; Ross et al, 2014; Ross and Tabrizi, 2011; van der Burg et al, 2009). The disease typically onsets in the 3rd to 4th decade of life, progresses over 15–20 years, and always leads to death (Ross et al, 2014)

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