Calcium Entry and α-Synuclein Inclusions Elevate Dendritic Mitochondrial Oxidant Stress in Dopaminergic Neurons
Calcium Entry and α-Synuclein Inclusions Elevate Dendritic Mitochondrial Oxidant Stress in Dopaminergic Neurons
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DOI：
10.1523/jneurosci.5311-12.2013
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发表时间：
2013-06-12
影响因子：
5.3
通讯作者：
Surmeier, D. James
中科院分区：
文献类型：
--
作者：
Dryanovski, Dilyan I.;Guzman, Jaime N.;Surmeier, D. James
帕金森病（PD）的核心运动症状可归因于黑质丘脑部（SNc）多巴胺能神经元的变性。线粒体氧化应激被广泛认为是PD发病机制的一个主要因素。以前的工作表明，通过L型通道的活性依赖性钙进入提高SNc多巴胺能神经元的核周线粒体氧化应激，为其选择性脆弱性提供了潜在的基础。什么是不太清楚的是，这种生理压力是否存在于树突，如果路易体，在PD brains中发现的主要神经病理学病变，加剧it. To追求这些问题，中脑多巴胺能神经元来自C57 BL/6转基因小鼠进行了研究，在原代培养，允许可视化的索马和树突同时。许多关键的功能，在体内成年多巴胺能神经元在体外重演。活动依赖性钙离子通过L-型通道进入增加了树突中的线粒体氧化应激。这种应力随着离索马的距离而逐渐增加。在脑切片中离体检查SNc多巴胺能神经元证实了这种模式。此外，细胞内α-突触核蛋白路易体样聚集体的形成增加了核周和树突状隔室中的线粒体氧化应激。这种压力似乎是extramitodulite的起源，因为清除剂的胞质活性氧或抑制NADPH oxidase衰减it. These结果表明，生理和蛋白质抑制应激可以添加剂在索马和树突的脆弱的多巴胺能神经元，PD发病机制的潜在因素提供了新的见解。
The core motor symptoms of Parkinson's disease (PD) are attributable to the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial oxidant stress is widely viewed a major factor in PD pathogenesis. Previous work has shown that activity-dependent calcium entry through L-type channels elevates perinuclear mitochondrial oxidant stress in SNc dopaminergic neurons, providing a potential basis for their selective vulnerability. What is less clear is whether this physiological stress is present in dendrites and if Lewy bodies, the major neuropathological lesion found in PD brains, exacerbate it. To pursue these questions, mesencephalic dopaminergic neurons derived from C57BL/6 transgenic mice were studied in primary cultures, allowing for visualization of soma and dendrites simultaneously. Many of the key features of in vivo adult dopaminergic neurons were recapitulated in vitro. Activity-dependent calcium entry through L-type channels increased mitochondrial oxidant stress in dendrites. This stress progressively increased with distance from the soma. Examination of SNc dopaminergic neurons ex vivo in brain slices verified this pattern. Moreover, the formation of intracellular alpha-synuclein Lewy-body-like aggregates increased mitochondrial oxidant stress in perinuclear and dendritic compartments. This stress appeared to be extramitochondrial in origin, because scavengers of cytosolic reactive oxygen species or inhibition of NADPH oxidase attenuated it. These results show that physiological and proteostatic stress can be additive in the soma and dendrites of vulnerable dopaminergic neurons, providing new insight into the factors underlying PD pathogenesis.