Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2.
Mouse midbrain dopaminergic neurons survive loss of the PD-associated mitochondrial protein CHCHD2.
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DOI：
10.1093/hmg/ddab329
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发表时间：
2021-11
影响因子：
3.5
通讯作者：
Mai K Nguyen;Kevin McAvoy;Szu-Chi Liao;Z. Doric;Iris Lo;Huihui Li;G. Manfredi;Ken Nakamura-Ken-Nakamur
中科院分区：
文献类型：
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作者：
Mai K Nguyen;Kevin McAvoy;Szu-Chi Liao;Z. Doric;Iris Lo;Huihui Li;G. Manfredi;Ken Nakamura-Ken-Nakamur
线粒体蛋白CHCHD2的突变导致常染色体显性遗传性帕金森病，其特征是黑质多巴胺(DA)神经元的优先丢失。因此，了解CHCHD2在神经元中的功能可能为了解线粒体功能障碍如何导致帕金森病患者的神经退变提供重要的见解。为了研究神经元对CHCHD2的正常需求和功能，我们首先检测了CHCHD2的水平，结果表明，无论是在体内还是在共同培养的情况下，DA神经元的CHCHD2水平都高于其他类型的神经元。然后，我们产生了在DA神经元中靶向缺失CHCHD2的小鼠，或者在大脑或整个身体中缺失CHCHD2。这三种模型都是可行的，大脑中CHCHD2的缺失不会导致DA神经元的退化。在DA神经元中缺乏CHCHD2的小鼠确实表现出性别特异性的运动活动变化，但我们没有观察到在肌肉力量、运动耐力或运动协调性的分析方面的差异。此外，缺乏CHCHD2的小鼠的线粒体没有表现出OXPHOS功能的异常。最后，由于CHCHD10和CHCHD2的缺失都不会导致中脑DA神经元的退化，因此CHCHD2缺失的恢复能力不能用其类似的CHCHD10的功能互补来解释。这些发现支持致病CHCHD2突变通过毒性功能获得机制而不是功能丧失机制导致帕金森病的假说。
Mutations in the mitochondrial protein CHCHD2 cause autosomal-dominant PD characterized by the preferential loss of substantia nigra dopamine (DA) neurons. Therefore, understanding the function of CHCHD2 in neurons may provide vital insights into how mitochondrial dysfunction contributes to neurodegeneration in PD. To investigate the normal requirement and function of CHCHD2 in neurons, we first examined CHCHD2 levels, and showed that DA neurons have higher CHCHD2 levels than other neuron types, both in vivo and in co-culture. We then generated mice with either a targeted deletion of CHCHD2 in DA neurons, or a deletion in the brain or total body. All three models were viable, and loss of CHCHD2 in the brain did not cause degeneration of DA neurons. Mice lacking CHCHD2 in DA neurons did display sex-specific changes to locomotor activity, but we did not observe differences in assays of muscle strength, exercise endurance, or motor coordination. Furthermore, mitochondria derived from mice lacking CHCHD2 did not display abnormalities in OXPHOS function. Lastly, resilience to CHCHD2 deletion could not be explained by functional complementation by its paralog CHCHD10, as deletion of both CHCHD10 and CHCHD2 did not cause degeneration of DA neurons in the midbrain. These findings support the hypothesis that pathogenic CHCHD2 mutations cause PD through a toxic gain-of-function, rather than loss-of-function mechanism.