title: Accumulation of STIM1 is associated with the degenerative muscle fibre phenotype in ALS and other neurogenic atrophies.
abstract: OBJECTIVE
  Upon denervation, skeletal muscle fibres initiate complex changes in gene expression. Many of these genes are involved in muscle fibre remodelling and atrophy. Amyotrophic lateral sclerosis (ALS) leads to progressive neurodegeneration and neurogenic muscular atrophy (NMA). Disturbed calcium homeostasis and misfolded protein aggregation both in motor neurones and muscle fibres are key elements of ALS pathogenesis that are mutually interdependent. Therefore, we hypothesized that the calcium sensor STIM1 might be abnormally modified and involved in muscle fibre degeneration in ALS and other types of NMA.
  
  
  METHODS
  We examined ALS and NMA patient biopsy and autopsy tissue and tissue from G93A SOD1 mice by immunohistochemistry and immunoblotting.
  
  
  RESULTS
  In normal human and mouse muscle STIM1 was found to be differentially expressed in muscle fibres of different types and to concentrate at neuromuscular junctions, compatible with its known role in calcium sensing. Denervated muscle fibres of sALS and NMA cases and SOD1 mice showed diffusely increased STIM1 immunoreactivity along with ubiquitinated material. In addition, distinct focal accumulations of STIM1 were observed in target structures within denervated fibres of sALS and other NMA as well as SOD1 mouse muscles. Large STIM1-immunoreactive structures were found in ALS-8 patient muscle harbouring the P56S mutation in the ER protein VAPB.
  
  
  CONCLUSIONS
  These findings suggest that STIM1 is involved in several ways in the reaction of muscle fibres to denervation, probably reflecting alterations in calcium homeostasis in denervated muscle fibres.
authors: Institute of Neuropathology, RWTH Aachen University and JARA Brain Translational Medicine, Aachen, Germany.
authors: Anand
authors: A
authors: Goswami
authors: Christofer Marvin
authors: CM
authors: Jesse
authors: Akila
authors: A
authors: Chandrasekar
authors: Eva
authors: E
authors: Bushuven
authors: Jan Tilmann
authors: JT
authors: Vollrath
authors: Alice
authors: A
authors: Dreser
authors: Istvan
authors: I
authors: Katona
authors: Cordian
authors: C
authors: Beyer
authors: Sonja
authors: S
authors: Johann
authors: A C
authors: AC
authors: Feller
authors: M
authors: M
authors: Grond
authors: S
authors: S
authors: Wagner
authors: Stefan
authors: S
authors: Nikolin
authors: Dirk
authors: D
authors: Troost
authors: Joachim
authors: J
authors: Weis
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism*; D010641:Phenotype; D000071737:Stromal Interaction Molecule 1
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; C103530:STIM1 protein, human; D000071737:Stromal Interaction Molecule 1
keywords: ALS; STIM1; calcium homeostasis; denervation; neurogenic muscular atrophy; tubular aggregate myopathy