Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy.

Karli Montague,Gyorgy Szabadkai,Bilal Malik,Albert R La Spada,Michael G Hanna,Anna L Gray,Linda Greensmith

doi:10.1093/brain/awu114

Abstract

Spinal and bulbar muscular atrophy is an X-linked degenerative motor neuron disease caused by an abnormal expansion in the polyglutamine encoding CAG repeat of the androgen receptor gene. There is evidence implicating endoplasmic reticulum stress in the development and progression of neurodegenerative disease, including polyglutamine disorders such as Huntington's disease and in motor neuron disease, where cellular stress disrupts functioning of the endoplasmic reticulum, leading to induction of the unfolded protein response. We examined whether endoplasmic reticulum stress is also involved in the pathogenesis of spinal and bulbar muscular atrophy. Spinal and bulbar muscular atrophy mice that carry 100 pathogenic polyglutamine repeats in the androgen receptor, and develop a late-onset neuromuscular phenotype with motor neuron degeneration, were studied. We observed a disturbance in endoplasmic reticulum-associated calcium homeostasis in cultured embryonic motor neurons from spinal and bulbar muscular atrophy mice, which was accompanied by increased endoplasmic reticulum stress. Furthermore, pharmacological inhibition of endoplasmic reticulum stress reduced the endoplasmic reticulum-associated cell death pathway. Examination of spinal cord motor neurons of pathogenic mice at different disease stages revealed elevated expression of markers for endoplasmic reticulum stress, confirming an increase in this stress response in vivo. Importantly, the most significant increase was detected presymptomatically, suggesting that endoplasmic reticulum stress may play an early and possibly causal role in disease pathogenesis. Our results therefore indicate that the endoplasmic reticulum stress pathway could potentially be a therapeutic target for spinal and bulbar muscular atrophy and related polyglutamine diseases.

Highlights

Spinal and bulbar muscular atrophy (SBMA), known as Kennedy’s disease, is an X-linked degenerative motor neuron disease caused by a polyglutamine encoding CAG repeat expansion in exon 1 of the androgen receptor gene (La Spada et al, 1991)
To examine the role of endoplasmic reticulum stress in SBMA, we first measured the levels of Ca2 + within the cytoplasm and endoplasmic reticulum of cultured embryonic motor neurons derived from wild-type and AR100 SBMA mice
The results presented in this study show that dysregulation of Ca2 + homeostasis in motor neurons of SBMA AR100 mice resulted in endoplasmic reticulum stress, which in turn increased the vulnerability of AR100 motor neurons to activation of endoplasmic reticulum-stress-induced apoptosis

Summary

Introduction

Spinal and bulbar muscular atrophy (SBMA), known as Kennedy’s disease, is an X-linked degenerative motor neuron disease caused by a polyglutamine encoding CAG repeat expansion in exon 1 of the androgen receptor gene (La Spada et al, 1991). Symptoms resulting from loss of lower motor neurons in the spinal cord and brainstem manifest primarily in males between 30 and 50 years of age and include proximal limb and bulbar muscle weakness, atrophy and fasciculations (Katsuno et al, 2012; Rocchi and Pennuto, 2013). Expansion of the polyglutamine repeat tract in the androgen receptor results in a pathogenic conformational change in the androgen receptor protein, facilitating its aggregation into inclusions (Perutz et al, 1994; Williams and Paulson, 2008). The precise mechanisms involved in the death of motor neurons in SBMA are unknown, the endoplasmic reticulum stress response has been shown to play a role in the pathogenesis of other motor neuron disorders, such as amyotrophic lateral sclerosis (Saxena et al, 2009) as well as polyglutamine diseases such as Huntington’s disease (Stenoien et al, 1999; Duennwald and Lindquist, 2008; Reijonen et al, 2008)

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