iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.
iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease.
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DOI：
10.1371/journal.pone.0184104
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Wray S
中科院分区：
文献类型：
--
作者：
Arber C;Angelova PR;Wiethoff S;Tsuchiya Y;Mazzacuva F;Preza E;Bhatia KP;Mills K;Gout I;Abramov AY;Hardy J;Duce JA;Houlden H;Wray S
PANK 2的突变导致神经变性和脑铁积累。PANK 2在从膳食维生素B5生物合成辅酶A（CoA）中起作用，但铁积累的神经病理机制和原因仍不清楚。在这项研究中，将非典型患者来源的成纤维细胞重编程为诱导多能干细胞（iPSC），随后分化为皮质神经元细胞，用于研究人类神经元的疾病机制。我们观察到对照和患者细胞之间PANK 2表达没有变化，但患者细胞中蛋白水平明显降低。CoA稳态和细胞铁处理正常，线粒体功能受到影响;表现为激活的NADH相关呼吸和抑制的FADH相关呼吸，导致线粒体膜电位升高。这导致患者源性神经元中活性氧生成和脂质过氧化增加。这些数据表明，线粒体缺陷是疾病过程的早期特征，可以通过改变NADH/FADH底物供应氧化磷酸化来解释。有趣的是，铁螯合似乎加剧了控制和患者神经元细胞中的线粒体表型。这就提醒了在没有铁积累的情况下，一般使用铁螯合疗法的谨慎性。
Mutations in PANK2 lead to neurodegeneration with brain iron accumulation. PANK2 has a role in the biosynthesis of coenzyme A (CoA) from dietary vitamin B5, but the neuropathological mechanism and reasons for iron accumulation remain unknown. In this study, atypical patient-derived fibroblasts were reprogrammed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into cortical neuronal cells for studying disease mechanisms in human neurons. We observed no changes in PANK2 expression between control and patient cells, but a reduction in protein levels was apparent in patient cells. CoA homeostasis and cellular iron handling were normal, mitochondrial function was affected; displaying activated NADH-related and inhibited FADH-related respiration, resulting in increased mitochondrial membrane potential. This led to increased reactive oxygen species generation and lipid peroxidation in patient-derived neurons. These data suggest that mitochondrial deficiency is an early feature of the disease process and can be explained by altered NADH/FADH substrate supply to oxidative phosphorylation. Intriguingly, iron chelation appeared to exacerbate the mitochondrial phenotype in both control and patient neuronal cells. This raises caution for the use iron chelation therapy in general when iron accumulation is absent.
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影响因子：
64.5
作者：
Duce JA;Tsatsanis A;Cater MA;James SA;Robb E;Wikhe K;Leong SL;Perez K;Johanssen T;Greenough MA;Cho HH;Galatis D;Moir RD;Masters CL;McLean C;Tanzi RE;Cappai R;Barnham KJ;Ciccotosto GD;Rogers JT;Bush AI
通讯作者：
Bush AI
影响因子：
3.7
作者：
Leonardi R;Rehg JE;Rock CO;Jackowski S
通讯作者：
Jackowski S
影响因子：
5
作者：
Arber CE;Li A;Houlden H;Wray S
通讯作者：
Wray S
影响因子：
6.1
作者：
Poli, Maura;Derosas, Manuela;Arosio, Paolo
通讯作者：
Arosio, Paolo
DOI：
10.1007/978-1-4939-2257-4_23
发表时间：
2015-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Bartolome, Fernando;Abramov, Andrey Y
通讯作者：
Abramov, Andrey Y