Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson’s disease

Molecular Neurodegeneration

David I Finkelstein¹  Ashley I Bush¹  Robert A Cherny¹  Irene Volitakis¹  Paul A Adlard¹  Peng Lei¹  Scott Ayton¹ 

[1] Florey Institute for Neuroscience and Mental Health, The University of Melbourne, Melbourne, Victoria, Australia

关键词: Age;    Ceruloplasmin;    Iron;    Parkinson’s disease;   

Others  :  869859
DOI  :  10.1186/1750-1326-9-27

 received in 2014-04-17, accepted in 2014-07-01,  发布年份 2014

【 摘 要 】

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.

Findings

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.

【 授权许可】

   
2014 Ayton et al.; licensee BioMed Central Ltd.

【 图 表 】

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