title: Endoplasmic reticulum stress in spinal and bulbar muscular atrophy: a potential target for therapy.
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.
authors.affiliation: 1 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK2 MRC Centre for Neuromuscular Diseases, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK.
authors.forename: Karli
authors.initials: K
authors.lastname: Montague
authors.affiliation: 1 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK2 MRC Centre for Neuromuscular Diseases, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK.
authors.forename: Bilal
authors.initials: B
authors.lastname: Malik
authors.affiliation: 1 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK2 MRC Centre for Neuromuscular Diseases, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Gray
authors.affiliation: 3 Department of Paediatrics, University of California San Diego, La Jolla, CA 92093, USA4 Department of Cellular & Molecular Medicine and Neurosciences, University of California San Diego, La Jolla, CA 92093, USA5 Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093, USA6 Institute for Genomic Medicine, University of California San Diego, La Jolla, CA 92093, USA7 Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, CA 92093, USA8 Rady Children's Hospital, San Diego, CA 92123, USA.
authors.forename: Albert R
authors.initials: AR
authors.lastname: La Spada
authors.affiliation: 2 MRC Centre for Neuromuscular Diseases, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK9 Department of Molecular Neuroscience, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Hanna
authors.affiliation: 10 Cell and Developmental Biology Department, UCL, Gower Street, London, WC1E 6BT, UK11 Department of Biomedical Sciences, University of Padua and CNR Neuroscience Institute, Padua, Italy.
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Szabadkai
authors.affiliation: 1 Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK2 MRC Centre for Neuromuscular Diseases, Institute of Neurology, UCL, Queen Square, London, WC1N 3BG, UK l.greensmith@ucl.ac.uk.
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
mesh_terms: D000367:Age Factors; D000728:Androgens / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000870:Anterior Horn Cells / Q000503:physiopathology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020966:Muscular Disorders, Atrophic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013116:Spinal Cord / Q000473:pathology; D019284:Thapsigargin / Q000627:therapeutic use
chemical_list: D000728:Androgens; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D019284:Thapsigargin; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: SBMA; calcium; endoplasmic reticulum stress; motor neuron disease; polyglutamine expansions