Mutations in CHCHD2 cause α-synuclein aggregation
Mutations in CHCHD2 cause α-synuclein aggregation
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DOI：
10.1093/hmg/ddz241
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发表时间：
2019-12-01
影响因子：
3.5
通讯作者：
Hattori, Nobutaka
中科院分区：
文献类型：
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作者：
Ikeda, Aya;Nishioka, Kenya;Hattori, Nobutaka
CHCHD2 突变与家族性常染色体显性遗传帕金森病 (PD) 有关。该基因产物可能调节线粒体呼吸功能。然而，CHCHD2 突变诱导的线粒体功能障碍是否进一步产生 α-突触核蛋白病理尚不清楚。在这里，我们通过脑尸检、诱导多能干细胞 (iPSC) 和果蝇遗传学提供了令人信服的遗传证据，证明 PD 连锁 CHCHD2 T61I 突变诱导的线粒体功能障碍会促进 a-突触核蛋白聚集。对患有 CHCHD2 T61I 的个体进行尸检后发现，脑干、边缘区和新皮质中存在广泛的路易病理学，包括淀粉样斑块和神经原纤维缠结。在 CHCHD2 T61I 脑组织中观察到肌氨酰不溶性 α-突触核蛋白聚集体的显着积累，其程度与 α-突触核蛋白 (SNCA) 重复病例相当。 CHCHD2 T61I 脑组织中的 α-突触核蛋白原纤维的朊病毒样活性和形态与 SNCA 重复和散发性 PD 脑组织中的原纤维相似。在来自 CHCHD2 T61I iPSC 和缺乏 CHCHD2 直系同源物或表达人 CHCHD2 T61I 的果蝇的多巴胺能神经元培养物中再现了α-突触核蛋白不溶性。此外，异位α-突触核蛋白表达与CHCHD2缺失或T61I的组合增强了果蝇多巴胺能神经元的毒性，改变了蛋白水解途径。此外，CHCHD2 T61I 在果蝇中通过 α-突触核蛋白失去了线粒体定位。在患者大脑中也观察到 CHCHD2 T61I 的错误定位。我们的研究表明，CHCHD2 是决定 PD 病因中 α-突触核蛋白稳定性的重要线粒体因子。
Mutations in CHCHD2 are linked to a familial, autosomal dominant form of Parkinson's disease (PD). The gene product may regulate mitochondrial respiratory function. However, whether mitochondrial dysfunction induced by CHCHD2 mutations further yields alpha-synuclein pathology is unclear. Here, we provide compelling genetic evidence that mitochondrial dysfunction induced by PD-linked CHCHD2 T61I mutation promotes a-synuclein aggregation using brain autopsy, induced pluripotent stem cells (iPSCs) and Drosophila genetics. An autopsy of an individual with CHCHD2 T61I revealed widespread Lewy pathology with both amyloid plaques and neurofibrillary tangles that appeared in the brain stem, limbic regions and neocortex. A prominent accumulation of sarkosyl-insoluble alpha-synuclein aggregates, the extent of which was comparable to that of a case with alpha-synuclein (SNCA) duplication, was observed in CHCHD2 T61I brain tissue. The prion-like activity and morphology of alpha-synuclein fibrils from the CHCHD2 T61I brain tissue were similar to those of fibrils from SNCA duplication and sporadic PD brain tissues. a-Synuclein insolubilization was reproduced in dopaminergic neuron cultures from CHCHD2 T61I iPSCs and Drosophila lacking the CHCHD2 ortholog or expressing the human CHCHD2 T61I. Moreover, the combination of ectopic alpha-synuclein expression and CHCHD2 null or T61I enhanced the toxicity in Drosophila dopaminergic neurons, altering the proteolysis pathways. Furthermore, CHCHD2 T61I lost its mitochondrial localization by alpha-synuclein in Drosophila. The mislocalization of CHCHD2 T61I was also observed in the patient brain. Our study suggests that CHCHD2 is a significant mitochondrial factor that determines alpha-synuclein stability in the etiology of PD.