title: Low autophagy capacity implicated in motor system vulnerability to mutant superoxide dismutase.
abstract: BACKGROUND
  The motor system is selectively vulnerable to mutations in the ubiquitously expressed aggregation-prone enzyme superoxide dismutase-1 (SOD1).
  
  
  RESULTS
  Autophagy clears aggregates, and factors involved in the process were analyzed in multiple areas of the CNS from human control subjects (n = 10) and amyotrophic lateral sclerosis (ALS) patients (n = 18) with or without SOD1 mutations. In control subjects, the key regulatory protein Beclin 1 and downstream factors were remarkably scarce in spinal motor areas. In ALS patients, there was evidence of moderate autophagy activation and also dysregulation. These changes were largest in SOD1 mutation carriers. To explore consequences of low autophagy capacity, effects of a heterozygous deletion of Beclin 1 were examined in ALS mouse models expressing mutant SOD1s. This caused earlier SOD1 aggregation, onset of symptoms, motor neuron loss, and a markedly shortened survival. In contrast, the levels of soluble misfolded SOD1 species were reduced.
  
  
  CONCLUSIONS
  The findings suggest that an inherent low autophagy capacity might cause the vulnerability of the motor system, and that SOD1 aggregation plays a crucial role in the pathogenesis.
authors.affiliation: Department of Medical Biosciences, Umeå University, Building 6 M, 2nd Floor, Umeå, SE 901 85, Sweden.|Present Address: Department of Chemistry, Keio University, 3-14-1, Hiyoshi, Yokohama, 223-0061, Kanagawa, Japan.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Tokuda
authors.affiliation: Department of Medical Biosciences, Umeå University, Building 6 M, 2nd Floor, Umeå, SE 901 85, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Brännström
authors.affiliation: Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, SE 901 85, Sweden.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Andersen
authors.affiliation: Department of Medical Biosciences, Umeå University, Building 6 M, 2nd Floor, Umeå, SE 901 85, Sweden. stefan.marklund@medbio.umu.se.
authors.forename: Stefan L
authors.initials: SL
authors.lastname: Marklund
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology*; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics; D001343:Autophagy / Q000235:genetics*; D000071186:Beclin-1; D000073885:C9orf72 Protein; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D066263:Protein Aggregation, Pathological / Q000235:genetics; D011506:Proteins / Q000235:genetics; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics*; D057149:Ubiquitinated Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D000073885:C9orf72 Protein; C568651:C9orf72 protein, human; D011506:Proteins; D057149:Ubiquitinated Proteins; D013482:Superoxide Dismutase; D046988:Proteasome Endopeptidase Complex
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