title: Wnt and extraocular muscle sparing in amyotrophic lateral sclerosis.
abstract: OBJECTIVE
  The extraocular muscles (EOM) and their motor neurons are spared in amyotrophic lateral sclerosis (ALS). In limb muscle, axon retraction from the neuromuscular junctions occurs early in the disease. Wnts, a conserved family of secreted signaling molecules, play a critical role in neuromuscular junction formation. This is the first study to examine Wnt signaling for its potential involvement in maintenance of normal morphology in EOM in ALS.
  
  
  METHODS
  Extraocular muscle and limb muscle axons, neuromuscular junctions, and myofibers from control, aging, and ALS subjects and the SOD1(G93A) mouse model of ALS were quantified for their expression of Wnt1, Wnt3a, Wnt5a, Wnt7a, and β-catenin.
  
  
  RESULTS
  All four Wnt isoforms were expressed in most axon profiles in all human EOM. Significantly fewer were positive for Wnt1, Wnt3a, and Wnt7a in the human limb muscles. Similar differential patterns in Wnt myofiber expression were also seen except in the case of Wnt7a, where expression was elevated. In the SOD1(G93A) mouse, all four Wnt isoforms were significantly decreased in the neuromuscular junctions at the terminal stage compared to values in age-matched controls. β-Catenin was activated in a subset of myofibers in EOM and limb muscle in all subjects.
  
  
  CONCLUSIONS
  The differences in expression of Wnts in EOM and limb muscle, particularly at the neuromuscular junction level, suggest that they play a role in the pathophysiology of ALS. Collectively, the data support a role for signaling of Wnts in the preservation of the EOM in ALS and their dysregulation and the subsequent development of pathology in the ALS limb muscles.
authors.affiliation: Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, Minnesota, United States Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.
authors.forename: Linda K
authors.initials: LK
authors.lastname: McLoon
authors.affiliation: Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.
authors.forename: Vahid M
authors.initials: VM
authors.lastname: Harandi
authors.affiliation: Department of Medical Biosciences, Pathology, Umeå University, Umeå, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brännström
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.affiliation: Department of Integrative Medical Biology, Section for Anatomy, Umeå University, Umeå, Sweden.
authors.forename: Jing-Xia
authors.initials: JX
authors.lastname: Liu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009210:Myofibrils / Q000378:metabolism; D009469:Neuromuscular Junction / Q000378:metabolism; D009801:Oculomotor Muscles / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D055815:Young Adult; D051176:beta Catenin / Q000378:metabolism
chemical_list: D051153:Wnt Proteins; D051176:beta Catenin
keywords: SOD1G93A mice; Wnt; amyotrophic lateral sclerosis; beta-catenin; extraocular muscles; neuromuscular junctions; skeletal muscle