title: Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson's disease.
abstract: BACKGROUND
  The substantia nigra (SN) midbrain nucleus is constitutively iron rich. Iron levels elevate further with age, and pathologically in Parkinson's disease (PD). Iron accumulation in PD SN involves dysfunction of ceruloplasmin (CP), which normally promotes iron export. We previously showed that ceruloplasmin knockout (CP KO) mice exhibit Parkinsonian neurodegeneration (~30% nigral loss) by 6 months, which is prevented by iron chelation. Here, we explored whether known iron-stressors of the SN (1) aging and (2) MPTP, would exaggerate the lesion severity of CP KO mice.
  
  
  RESULTS
  We show that while 5 month old CP KO mice exhibited nigral iron elevation and loss of SN neurons, surprisingly, aging CP KO mice to 14 months did not exacerbate iron elevation or SN neuronal loss. Unlike young mice, iron chelation therapy in CP KO mice between 9-14 months did not rescue neuronal loss. MPTP exaggerated iron elevation in young CP KO mice but did not increase cell death when compared to WTs.
  
  
  CONCLUSIONS
  We conclude that there may exist a proportion of substantia nigra neurons that depend on CP for protection against iron neurotoxicity and could be protected by iron-based therapeutics. Death of the remaining neurons in Parkinson's disease is likely caused by parallel disease mechanisms, which may call for additional therapeutic options.
authors.forename: Scott
authors.initials: S
authors.lastname: Ayton
authors.forename: Peng
authors.initials: P
authors.lastname: Lei
authors.forename: Paul A
authors.initials: PA
authors.lastname: Adlard
authors.forename: Irene
authors.initials: I
authors.lastname: Volitakis
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
authors.forename: Ashley I
authors.initials: AI
authors.lastname: Bush
authors.affiliation: Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia. d.finkelstein@florey.edu.au.
authors.forename: David I
authors.initials: DI
authors.lastname: Finkelstein
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D001923:Brain Chemistry / Q000502:physiology; D002570:Ceruloplasmin / Q000172:deficiency / Q000235:genetics; D004195:Disease Models, Animal; D007501:Iron / Q000633:toxicity*; D019189:Iron Metabolism Disorders / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D020734:Parkinsonian Disorders / Q000473:pathology*; D013378:Substantia Nigra / Q000473:pathology*
chemical_list: D007501:Iron; D002570:Ceruloplasmin