iPSC-derived neuronal models of PANK2-associated neurodegeneration reveal mitochondrial dysfunction contributing to early disease

被引:38
作者
Arber, Charles [1 ]
Angelova, Plamena R. [1 ]
Wiethoff, Sarah [1 ]
Tsuchiya, Yugo [2 ]
Mazzacuva, Francesca [3 ]
Preza, Elisavet [1 ]
Bhatia, Kailash P. [1 ]
Mills, Kevin [3 ]
Gout, Ivan [2 ]
Abramov, Andrey Y. [1 ]
Hardy, John [1 ]
Duce, James A. [4 ]
Houlden, Henry [1 ]
Wray, Selina [1 ]
机构
[1] UCL, Dept Mol Neurosci, Inst Neurol, London, England
[2] UCL, Inst Struct & Mol Biol, London, England
[3] UCL Inst Child Hlth, Ctr Translat Omics, Genet & Genom Med Programme, London, England
[4] Univ Leeds, Sch Mol & Cellular Biol, Fac Biol Sci, Leeds, W Yorkshire, England
来源
PLOS ONE | 2017年 / 12卷 / 09期
基金
英国医学研究理事会; 英国生物技术与生命科学研究理事会; 英国惠康基金;
关键词
BRAIN IRON ACCUMULATION; COENZYME-A; PANTOTHENATE; INSIGHTS; METABOLISM; UPDATE; PANK2;
D O I
10.1371/journal.pone.0184104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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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页数:22
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