Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson's disease.
Iron accumulation confers neurotoxicity to a vulnerable population of nigral neurons: implications for Parkinson's disease.
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DOI：
10.1186/1750-1326-9-27
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发表时间：
2014-07-10
影响因子：
15.1
通讯作者：
Finkelstein DI
中科院分区：
文献类型：
--
作者：
Ayton S;Lei P;Adlard PA;Volitakis I;Cherny RA;Bush AI;Finkelstein DI
中脑核黑质（SN）是富铁的组成体。铁水平随着年龄的增长而进一步升高，在帕金森病（PD）中也是如此。PD - SN的铁积累涉及铜蓝蛋白功能障碍，而铜蓝蛋白通常促进铁的输出。我们之前的研究表明，铜蓝蛋白敲除（CP KO）小鼠在6个月时表现出帕金森神经变性（约30%的神经损失），铁螯合可以预防这种情况。在这里，我们探讨了已知的SN(1)老化和(2)MPTP的铁应激源是否会夸大CP KO小鼠的病变严重程度。我们发现，虽然5个月大的CP KO小鼠表现出神经性铁升高和SN神经元的丢失，但令人惊讶的是，衰老到14个月的CP KO小鼠并没有加剧铁升高或SN神经元的丢失。与幼鼠不同，9-14月龄CP KO小鼠的铁螯合治疗并没有挽救神经元的丧失。与WTs相比，MPTP增加了年轻CP KO小鼠的铁含量，但没有增加细胞死亡。我们得出结论，可能存在一定比例的黑质神经元依赖CP来保护铁神经毒性，并且可以通过铁基治疗来保护。帕金森病中剩余神经元的死亡可能是由平行的疾病机制引起的，这可能需要额外的治疗方案。
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. 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. 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.
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影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
11
作者：
ALBERCA, R;RAFEL, E;NAVARRO, A
通讯作者：
NAVARRO, A
影响因子：
15.8
作者：
Pichler I;Del Greco M F;Gögele M;Lill CM;Bertram L;Do CB;Eriksson N;Foroud T;Myers RH;PD GWAS Consortium;Nalls M;Keller MF;International Parkinson's Disease Genomics Consortium;Wellcome Trust Case Control Consortium 2;Benyamin B;Whitfield JB;Genetics of Iron Status Consortium;Pramstaller PP;Hicks AA;Thompson JR;Minelli C
通讯作者：
Minelli C
影响因子：
11.2
作者：
Ayton, Scott;Lei, Peng;Finkelstein, David I.
通讯作者：
Finkelstein, David I.
影响因子：
9.9
作者：
Hochstrasser, H;Bauer, P;Berg, D
通讯作者：
Berg, D