Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories.
Review: Insights into molecular mechanisms of disease in neurodegeneration with brain iron accumulation: unifying theories.
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DOI：
10.1111/nan.12242
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发表时间：
2016-04
影响因子：
5
通讯作者：
Wray S
中科院分区：
文献类型：
--
作者：
Arber CE;Li A;Houlden H;Wray S
神经变性伴脑铁蓄积(NBIA)是一组以肌张力障碍、帕金森氏症和痉挛为特征的疾病。铁聚集在基底节，根据NBIA亚型的不同，可能伴随着路易小体、轴突肿胀和过度磷酸化的tau。10个基因的突变与NBIA有关，包括直接参与铁稳态的铜蓝蛋白(CP)和铁蛋白轻链(FTL)，以及泛酸激酶2(PANK2)、磷脂酶A2组6(PLA2G6)、脂肪酸羟基酶2(FA2H)、辅酶A合成酶(COASY)、C19orf12、WDR 45和DCAF 17(C2 Orf37)。这些基因参与了看似不相关的细胞途径，如脂类代谢、辅酶A合成和自噬。需要对连接这些基因的细胞通路和导致铁代谢紊乱的疾病机制有更深入的了解。此外，NBIA和更常见的神经退行性疾病之间的主要重叠可能突出了保守的疾病过程。在这篇综述中，我们将讨论每个NBIA相关基因的临床和病理结果，讨论已提出的疾病机制，如线粒体健康、氧化损伤、自噬/有丝分裂吞噬和铁稳态，并推测NBIA亚型之间的潜在重叠。
Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders characterized by dystonia, parkinsonism and spasticity. Iron accumulates in the basal ganglia and may be accompanied by Lewy bodies, axonal swellings and hyperphosphorylated tau depending on NBIA subtype. Mutations in 10 genes have been associated with NBIA that include Ceruloplasmin (Cp) and ferritin light chain (FTL), both directly involved in iron homeostasis, as well as Pantothenate Kinase 2 (PANK2), Phospholipase A2 group 6 (PLA2G6), Fatty acid hydroxylase 2 (FA2H), Coenzyme A synthase (COASY), C 19orf12, WDR 45 and DCAF 17 (C 2orf37). These genes are involved in seemingly unrelated cellular pathways, such as lipid metabolism, Coenzyme A synthesis and autophagy. A greater understanding of the cellular pathways that link these genes and the disease mechanisms leading to iron dyshomeostasis is needed. Additionally, the major overlap seen between NBIA and more common neurodegenerative diseases may highlight conserved disease processes. In this review, we will discuss clinical and pathological findings for each NBIA‐related gene, discuss proposed disease mechanisms such as mitochondrial health, oxidative damage, autophagy/mitophagy and iron homeostasis, and speculate the potential overlap between NBIA subtypes.