Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, USA.
Nature. 2021 Nov;599(7886):650-656. doi: 10.1038/s41586-021-04059-0. Epub 2021 Nov 3.
Loss of functional mitochondrial complex I (MCI) in the dopaminergic neurons of the substantia nigra is a hallmark of Parkinson's disease. Yet, whether this change contributes to Parkinson's disease pathogenesis is unclear. Here we used intersectional genetics to disrupt the function of MCI in mouse dopaminergic neurons. Disruption of MCI induced a Warburg-like shift in metabolism that enabled neuronal survival, but triggered a progressive loss of the dopaminergic phenotype that was first evident in nigrostriatal axons. This axonal deficit was accompanied by motor learning and fine motor deficits, but not by clear levodopa-responsive parkinsonism-which emerged only after the later loss of dopamine release in the substantia nigra. Thus, MCI dysfunction alone is sufficient to cause progressive, human-like parkinsonism in which the loss of nigral dopamine release makes a critical contribution to motor dysfunction, contrary to the current Parkinson's disease paradigm.
功能性线粒体复合物 I（MCI）在黑质多巴胺能神经元中的丧失是帕金森病的一个标志。然而，这种变化是否导致帕金森病的发病机制尚不清楚。在这里，我们使用了交叉遗传方法来破坏小鼠多巴胺能神经元中的 MCI 功能。MCI 的破坏诱导了代谢的瓦博格样转变，使神经元存活，但触发了多巴胺能表型的进行性丧失，这首先在黑质纹状体轴突中明显。这种轴突缺陷伴随着运动学习和精细运动缺陷，但没有明显的左旋多巴反应性帕金森病——只有在黑质多巴胺释放的后期丧失后才会出现。因此，MCI 功能障碍本身足以导致进行性、类似人类的帕金森病，其中黑质多巴胺释放的丧失对运动功能障碍有至关重要的贡献，这与当前的帕金森病范式相反。
