The Parkinson's Disease-Related Protein DJ-1 Protects Dopaminergic Neurons in vivo and Cultured Cells from Alpha-Synuclein and 6-Hydroxydopamine Toxicity
The Parkinson's Disease-Related Protein DJ-1 Protects Dopaminergic Neurons in vivo and Cultured Cells from Alpha-Synuclein and 6-Hydroxydopamine Toxicity
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DOI：
10.1159/000367993
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发表时间：
2015-01-01
影响因子：
3
通讯作者：
Albani, Diego
中科院分区：
文献类型：
--
作者：
Batelli, Sara;Invernizzi, Roberto William;Albani, Diego
背景资料：多巴胺能变性是帕金森病（PD）患者大脑中的主要发现，与路易体、主要由原纤维蛋白α-突触核蛋白（alpha-syn）组成的神经元内内含物一起。据报道，家族PD相关蛋白DJ-1可减少由α-syn或多巴胺能选择性神经毒素6-羟基多巴胺（6-OHDA）引发的多巴胺能变性。目的：其目的是进一步研究DJ-1在多巴胺能变性中的作用，并观察DJ-1的细胞渗透性重组形式（TAT-DJ-1）是否可以恢复体内多巴胺耗竭，从而代表一种创新的治疗方法。研究方法：我们开发了体外（PC 12/TetOn细胞和小鼠原代中脑神经元）和体内模型[包括DJ-1敲除（-/-）小鼠]来研究DJ-1在多巴胺能变性中的作用。结果如下：我们发现，在过表达具有家族PD连锁突变A30 P的α-syn的PC 12/TetOn细胞中，DJ-1沉默增加了α-syn（A30 P）毒性。来自DJ-1（-/-）小鼠的原代中脑神经元更容易受到细胞可渗透形式的α-syn（TAT-α-syn）和6-OHDA的影响。纹状体内施用的TAT-DJ-1降低了C57 BL/6小鼠体内的6-OHDA毒性。最后，当我们在DJ-1（-/-）动物的纹状体中注射TAT-alpha-syn（A30 P）时，多巴胺的消耗比对照品系更多。结论：DJ-1似乎对由α-syn或6-OHDA触发的多巴胺能变性具有保护作用，加强了这种蛋白质在PD中的可能治疗重要性。(C)2014 S. Karger AG，巴塞尔
Background: Dopaminergic degeneration is a major finding in brains of patients with Parkinson's disease (PD), together with Lewy bodies, intraneuronal inclusions mainly composed of the fibrillogenic protein alpha-synuclein (alpha-syn). The familial-PD-related protein DJ-1 was reported to reduce dopaminergic degeneration triggered by alpha-syn or by the dopaminergic-selective neurotoxin 6-hydroxydopamine (6-OHDA). Objective: The aim was to further investigate the role of DJ-1 in dopaminergic degeneration and to see whether a cell-permeable recombinant form of DJ-1 (TAT-DJ-1) could restore dopamine depletion in vivo, thus representing an innovative therapeutic approach. Methods: We developed in vitro (PC12/TetOn cells and mouse primary mesencephalic neurons) and in vivo models [including DJ-1 knockout (-/-) mice] to investigate DJ-1 in dopaminergic degeneration. Results: We found that in PC12/TetOn cells overexpressing alpha-syn with the familial-PD linked mutation A30P, DJ-1 silencing increased alpha-syn (A30P) toxicity. Primary mesencephalic neurons from DJ-1 (-/-) mice were more vulnerable to a cell-permeable form of alpha-syn (TAT-alpha-syn) and to 6-OHDA. Intrastriatally administered TAT-DJ-1 reduced 6-OHDA toxicity in vivo in C57BL/6 mice. Finally, when we injected TAT-alpha-syn (A30P) in the striatum of DJ-1 (-/-) animals, dopamine was depleted more than in the control strain. Conclusion: DJ-1 appears to have a protective role against dopaminergic degeneration triggered by alpha-syn or 6-OHDA, reinforcing the possible therapeutic importance of this protein in PD. (C) 2014 S. Karger AG, Basel