Why dopamine-containing neurons of the brain's substantia nigra pars compacta die in Parkinson's disease has been an enduring mystery. Our studies suggest that the unusual reliance of these neurons on L-type Ca(v)1.3 Ca2+ channels to drive their maintained, rhythmic pacemaking renders them vulnerable to stressors thought to contribute to disease progression. The reliance on these channels increases with age, as juvenile dopamine-containing neurons in the substantia nigra pars compacta use pacemaking mechanisms common to neurons not affected in Parkinson's disease. These mechanisms remain latent in adulthood, and blocking Ca(v)1.3 Ca2+ channels in adult neurons induces a reversion to the juvenile form of pacemaking. Such blocking ('rejuvenation') protects these neurons in both in vitro and in vivo models of Parkinson's disease, pointing to a new strategy that could slow or stop the progression of the disease.

译文

为什么大脑黑质的含多巴胺神经元在帕金森氏病中死亡一直是一个持久的谜。我们的研究表明,这些神经元对L型Ca(v)1.3 Ca2通道的异常依赖,以驱动其维持的节律性起搏,使其容易受到被认为有助于疾病进展的应激源的影响。对这些通道的依赖随着年龄的增长而增加,因为黑质致密部中含有多巴胺的少年神经元使用了帕金森氏病未受影响的神经元常见的起搏机制。这些机制在成年期仍然是潜在的,并且在成年神经元中阻断Ca(v)1.3 Ca2通道会导致恢复到幼年的起搏形式。这种阻断 (“恢复活力”) 在帕金森氏病的体外和体内模型中保护这些神经元,这表明了一种可以减缓或阻止疾病进展的新策略。

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