Molecular pathogenesis of polymerase γ-related neurodegeneration.
Molecular pathogenesis of polymerase γ-related neurodegeneration.
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DOI：
10.1002/ana.24185
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发表时间：
2014-07
影响因子：
11.2
通讯作者：
Bindoff, Laurence A.
中科院分区：
文献类型：
--
作者：
Tzoulis, Charalampos;Gia Tuong Tran;Coxhead, Jonathan;Bertelsen, Bjorn;Lilleng, Peer K.;Balafkan, Novin;Payne, Brendan;Miletic, Hrvoje;Chinnery, Patrick F.;Bindoff, Laurence A.
聚合酶γ (POLG) 突变是线粒体疾病的常见原因，也与神经退行性变和衰老有关。我们使用大量患者的死后组织研究了 POLG 相关神经变性的分子机制。所有受试者均可获得临床信息。采用组织病理学、免疫组织化学和显微解剖神经元分子研究相结合的方法，对 15 名患者和 23 名对照者的福尔马林固定和冷冻脑组织进行了研究。神经元中 POLG 突变的主要后果是线粒体 DNA 耗竭。这种情况已经存在于婴儿身上，几乎没有神经元损失或线粒体功能障碍的证据。随着疾病持续时间的延长，我们发现线粒体 DNA 缺失和点突变逐渐积累，并伴随着复合 I 缺陷神经元数量的增加。进行性神经变性主要影响小脑系统和黑质的多巴胺能细胞。叠加在这个慢性过程上的是急性、局灶性皮质病变，与致癫痫病灶相关，并显示大量神经元损失。 POLG 突变似乎通过早期和稳定的耗竭以及线粒体基因组的渐进体细胞突变的结合来损害神经元呼吸。这导致了两个不同但重叠的生物过程：临床上表现为进行性共济失调和认知障碍的慢性神经变性，以及似乎与癫痫发作有关的急性局灶性神经元坏死。我们的研究结果为这种常见线粒体脑病的慢性急性临床病程提供了解释。安神经学 2014 年；76:66–81
Polymerase gamma (POLG) mutations are a common cause of mitochondrial disease and have also been linked to neurodegeneration and aging. We studied the molecular mechanisms underlying POLG-related neurodegeneration using postmortem tissue from a large number of patients. Clinical information was available from all subjects. Formalin-fixed and frozen brain tissue from 15 patients and 23 controls was studied employing a combination of histopathology, immunohistochemistry, and molecular studies of microdissected neurons. The primary consequence of POLG mutation in neurons is mitochondrial DNA depletion. This was already present in infants with little evidence of neuronal loss or mitochondrial dysfunction. With longer disease duration, we found an additional, progressive accumulation of mitochondrial DNA deletions and point mutations accompanied by increasing numbers of complex I–deficient neurons. Progressive neurodegeneration primarily affected the cerebellar systems and dopaminergic cells of the substantia nigra. Superimposed on this chronic process were acute, focal cortical lesions that correlated with epileptogenic foci and that showed massive neuronal loss. POLG mutations appear to compromise neuronal respiration via a combination of early and stable depletion and a progressive somatic mutagenesis of the mitochondrial genome. This leads to 2 distinct but overlapping biological processes: a chronic neurodegeneration reflected clinically by progressive ataxia and cognitive impairment, and an acute focal neuronal necrosis that appears to be related to the presence of epileptic seizures. Our findings offer an explanation of the acute-on-chronic clinical course of this common mitochondrial encephalopathy. ANN NEUROL 2014;76:66–81
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影响因子：
4.4
作者：
Balafkan, Novin;Tzoulis, Charalampos;Bindoff, Laurence A.
通讯作者：
Bindoff, Laurence A.
影响因子：
14.5
作者：
Tzoulis, Charalampos;Neckelmann, Gesche;Bindoff, Laurence A.
通讯作者：
Bindoff, Laurence A.
影响因子：
14.5
作者：
Ferrari, G;Lamantea, E;Zeviani, M
通讯作者：
Zeviani, M
影响因子：
6
作者：
Wiest, Roland;Estermann, Lea;Hauf, Martinus
通讯作者：
Hauf, Martinus
影响因子：
9.8
作者：
Hakonen, AH;Heiskanen, S;Suomalainen, A
通讯作者：
Suomalainen, A