帕金森病黑质多巴胺神经元易损伤性的内在因素

Inherent Factors of Dopaminergic Neurons Vulnerability in the Substantia Nigra of Parkinson’s Disease

帕金森病(Parkinson’s disease,PD)主要症状是由中脑黑质致密部(substantia nigra compact,SNc)的多巴胺(dopamine,DA)神经元死亡引起。帕金森病发病过程中,路易小体病理(Lewy pathology,LP)和线粒体功能障碍最为突出,但SNc多巴胺神经元为什么特别易遭受这两种病理损害尚不清楚。研究表明,与脑内其他神经元相比,SNc多巴胺神经元具有特殊的解剖形态、生理和生化表型。SNc多巴胺神经元具有高分支无髓鞘轴突和众多的突触终端,突触末梢物质和能量代谢的高要求需要大量的线粒体,巨大突触终端增加了突触蛋白质的表达、转运和降解的负担。SNc多巴胺神经元具有独特的自主起搏电活动和缓慢钙振荡特性,Cav1. 3钙通道活动及后续的级联反应增加了SNc多巴胺神经元线粒体负担,增加了基础氧化应激、线粒体损伤和自噬,降低了处理错误折叠蛋白质的能力。SNc多巴胺神经元特有的神经递质--多巴胺易被氧化成为反应性醌,具有潜在毒性,可破坏葡糖脑苷脂酶导致其活性降低,引起线粒体氧化应激和溶酶体功能障碍。总之,SNc多巴胺神经元具有的这些内在因素综合起来,可能导致了其对线粒体功能障碍和路易小体病理损伤的易感性,并且SNc多巴胺神经元所处的神经网络障碍也促使了帕金森病的进展。认识到这些特征会对研究帕金森病相关病理学机制和阻止疾病进展创造新的机会。

The main symptoms of Parkinson’s disease( PD) result from dopamine( DA) neuron loss in the substantia nigra compact( SNc) of the midbrain. In the pathogenesis of PD,two pathological mechanisms,Lewy pathology( LP) and mitochondrial dysfunction,are most prominent,but it remains unclear why SNc DA neurons are particularly vulnerable to these two pathological damages. Recent studies have shown that compared with other neurons in the brain,SNc DA neurons have special anatomical, physiological and biochemical phenotypes. SNc DA neurons have high branched unmyelinated axons and numerous synaptic terminals. The high requirement of substance and energy metabolism of synaptic terminals requires a large number of mitochondria. Giant synaptic terminals increase the burden of synaptic protein expression,transport and degradation. The unique spontaneous pacemaker potential and slow calcium oscillation are two typical electrophysiological characteristics of SNc DA neurons. Cav1. 3 calcium channel activation and subsequent cascade reaction increase the mitochondrial burden of SNc DA neurons,elevate basic oxidative stress,promote mitochondrial damage and autophagy,and reduce the ability to deal with misfolded proteins. DA,a peculiar neurotransmitter to SNc DA neurons,is easily oxidized to reactive quinones with potential toxicity. DA quinones can also destroy the activity of glucocerebrosidase, resulting in mitochondrial oxidative stress and lysosome dysfunction. In summary,these inherent factors of SNc DA neurons may lead to their vulnerability to mitochondrial dysfunction and LP,and the neuronal network disorders of SNc DA neurons also promote the progress of PD. Recognizing these characteristics may create new opportunities for studying PD-related pathological mechanisms and developing therapeutics to slow or prevent disease progression.