The effects of pdr1, djr1.1 and pink1 loss in manganese-induced toxicity and the role of α-synuclein in C-elegans
The effects of pdr1, djr1.1 and pink1 loss in manganese-induced toxicity and the role of α-synuclein in C-elegans
复制标题
DOI：
10.1039/c3mt00325f
复制
发表时间：
2014-01-01
期刊：
影响因子：
3.4
通讯作者：
Aschner, Michael
中科院分区：
文献类型：
--
作者：
Bornhorst, Julia;Chakraborty, Sudipta;Aschner, Michael
帕金森病（PD）是一种神经退行性脑疾病，其特征在于选择性多巴胺能（DA能）细胞损失，导致明显的运动和认知缺陷。目前的治疗方案存在对抗PD肿瘤学，但由于缺乏有关其病因学的知识，无法直接靶向其发病机制。有几个基因与PD有关，包括三个与早发性家族形式相关的基因：parkin，pink 1和dj 1。所有这三个基因都参与调节氧化应激途径。PD病理生理学的另一个标志是路易体沉积，与功能获得性遗传风险因子α-突触核蛋白相关。α-突触核蛋白的功能知之甚少，因为它在PD中显示神经毒性和神经保护活性。利用遗传学上易处理的无脊椎动物秀丽隐杆线虫（C. elegans）模型系统中，在突变的pdr 1、pink 1或djr 1.1的背景下，检查了α-突触核蛋白在急性Mn暴露时的神经毒性或神经保护作用。pdr 1和djr1.1突变体表现出增强的锰积累和氧化应激，减少了α-突触核蛋白。此外，DA能神经变性，而与锰暴露不变，恢复到野生型（WT）水平的pdr 1，但不是djr1.1突变体表达α-突触核蛋白。总之，该研究揭示了WT人α-突触核蛋白在PD相关基因背景下减弱Mn诱导的毒性中的新的神经保护作用，并进一步支持细胞外多巴胺在加剧Mn神经毒性中的作用。
Parkinson's disease (PD) is a neurodegenerative brain disorder characterized by selective dopaminergic (DAergic) cell loss that results in overt motor and cognitive deficits. Current treatment options exist to combat PD symptomatology, but are unable to directly target its pathogenesis due to a lack of knowledge concerning its etiology. Several genes have been linked to PD, including three genes associated with an early-onset familial form: parkin, pink1 and dj1. All three genes are implicated in regulating oxidative stress pathways. Another hallmark of PD pathophysiology is Lewy body deposition, associated with the gain-of-function genetic risk factor a-synuclein. The function of a-synuclein is poorly understood, as it shows both neurotoxic and neuroprotective activities in PD. Using the genetically tractable invertebrate Caenorhabditis elegans (C. elegans) model system, the neurotoxic or neuroprotective role of a-synuclein upon acute Mn exposure in the background of mutated pdr1, pink1 or djr1.1 was examined. The pdr1 and djr1.1 mutants showed enhanced Mn accumulation and oxidative stress that was reduced by a-synuclein. Moreover, DAergic neurodegeneration, while unchanged with Mn exposure, returned to wild-type (WT) levels for pdr1, but not djr1.1 mutants expressing a-synuclein. Taken together, this study uncovers a novel, neuroprotective role for WT human a-synuclein in attenuating Mn-induced toxicity in the background of PD-associated genes, and further supports the role of extracellular dopamine in exacerbating Mn neurotoxicity.