title: Complement activation at the motor end-plates in amyotrophic lateral sclerosis.
abstract: BACKGROUND
  Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease with no available therapy. Components of the innate immune system are activated in the spinal cord and central nervous system of ALS patients. Studies in the SOD1(G93A) mouse show deposition of C1q and C3/C3b at the motor end-plate before neurological symptoms are apparent, suggesting that complement activation precedes neurodegeneration in this model. To obtain a better understanding of the role of complement at the motor end-plates in human ALS pathology, we analyzed post-mortem tissue of ALS donors for complement activation and its regulators.
  
  
  METHODS
  Post-mortem intercostal muscle biopsies were collected at autopsy from ALS (n = 11) and control (n = 6) donors. The samples were analyzed for C1q, membrane attack complex (MAC), CD55, and CD59 on the motor end-plates, using immunofluorescence or immunohistochemistry.
  
  
  RESULTS
  Here, we show that complement activation products and regulators are deposited on the motor end-plates of ALS patients. C1q co-localized with neurofilament in the intercostal muscle of ALS donors and was absent in controls (P = 0.001). In addition, C1q was found deposited on the motor end-plates in the intercostal muscle. MAC was also found deposited on motor end-plates that were innervated by nerves in the intercostal muscle of ALS donors but not in controls (P = 0.001). High levels of the regulators CD55 and CD59 were detected at the motor end-plates of ALS donors but not in controls, suggesting an attempt to counteract complement activation and prevent MAC deposition on the end-plates before they are lost.
  
  
  CONCLUSIONS
  This study provides evidence that complement activation products are deposited on innervated motor end-plates in the intercostal muscle of ALS donors, indicating that complement activation may precede end-plate denervation in human ALS. This study adds to the understanding of ALS pathology in man and identifies complement as a potential modifier of the disease process.
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Nawal
authors.initials: N
authors.lastname: Bahia El Idrissi
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Bosch
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Valeria
authors.initials: V
authors.lastname: Ramaglia
authors.affiliation: Department of Neuropathology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.affiliation: Department of Genome Analysis, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands. f.baas@amc.nl.
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.affiliation: Department of Neuropathology, Academic Medical Center, Amsterdam, 1105 AZ, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000503:physiopathology*; D000818:Animals; D001706:Biopsy; D018958:CD55 Antigens / Q000378:metabolism; D018957:CD59 Antigens / Q000378:metabolism; D003167:Complement Activation; D015922:Complement C1q / Q000378:metabolism; D015938:Complement Membrane Attack Complex / Q000378:metabolism; D005260:Female; D006801:Humans; D007366:Intercostal Muscles / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D009045:Motor Endplate; D016900:Neurofilament Proteins / Q000378:metabolism; D000072105:Superoxide Dismutase-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D018958:CD55 Antigens; D018957:CD59 Antigens; D015938:Complement Membrane Attack Complex; D016900:Neurofilament Proteins; D015922:Complement C1q; C000606291:Sod1 protein, mouse; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; C1q; CD55; CD59; Complement; MAC; Motor end-plates