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

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Karli Montague, Bilal Malik, Anna L. Gray, Albert R. La Spada, Michael G. Hanna, Gyorgy Szabadkai, Linda Greensmith
DOI: http://dx.doi.org/10.1093/brain/awu114 1894-1906 First published online: 4 June 2014

Summary

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.

  • endoplasmic reticulum stress
  • polyglutamine expansions
  • motor neuron disease
  • calcium
  • SBMA
  • Abbreviations
    AR100
    androgen receptor with pathogenic 100 glutamine repeat
    BiP
    binding immunoglobulin protein
    CHOP
    CCAAT/enhancer binding protein-homologous protein
    PERK
    protein kinase RNA-like endoplasmic reticulum kinase
    SBMA
    spinal and bulbar muscular atrophy
    SERCA
    sarcoendoplasmic reticulum Ca2+ ATPase
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