Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson's disease
Brain region specific mitophagy capacity could contribute to selective neuronal vulnerability in Parkinson's disease
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DOI：
10.1186/1477-5956-9-59
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发表时间：
2011-09-23
期刊：
影响因子：
2
通讯作者：
Mao, Lei
中科院分区：
文献类型：
--
作者：
Diedrich, Madeleine;Kitada, Tohru;Mao, Lei
帕金森病(PD)的组织学特征是黑质致密部多巴胺能神经元的变性。值得注意的是，与帕金森病相关的不同突变可以产生类似的大脑区域特定病理。这表明存在一些固有的关于差异神经元脆弱性的区域特异性，这共同决定了疾病的进展。为了深入了解帕金森病的发病机制，我们研究了帕金森病小鼠模型PINK1基因敲除小鼠(PINK1-KO)和野生型对照小鼠三个不同脑区的蛋白质表达和蛋白质氧化模式。PINK1功能障碍可能通过干扰线粒体自噬途径影响线粒体周转。被研究的三个大脑区域是中脑，它是黑质的位置；纹状体，黑质的主要传出区域；以及大脑皮层，它更远离帕金森病的病理。在所有这三个区域，负责能量代谢和膜电位的线粒体蛋白在PINK1-KO小鼠中都发生了显著变化，但在上调/下调方面具有非常不同的区域特异性口音。这表明，由PINK1基因敲除引起的异常的有丝分裂可能对不同的大脑区域有不同的影响。具体地说，中脑组织似乎受到线粒体周转缺陷的最严重打击，而皮质和纹状体可以通过反馈刺激其他分解代谢程序来弥补吞丝功能的丧失。此外，在PINK1-KO和野生型小鼠中，大脑皮层组织的蛋白质氧化水平最低，这表明该脑区具有更好的氧化保护或较低的活性氧(ROS)压力。正常小鼠大脑超微结构组织学检查显示，大脑皮层有丝分裂空泡的发生率高于纹状体和黑质。综上所述，不同脑区氧化保护和吞丝分裂能力之间的微妙平衡可能有助于帕金森病患者脑区特有的病理模式。
Parkinson's disease (PD) is histologically well defined by its characteristic degeneration of dopaminergic neurons in the substantia nigra pars compacta. Remarkably, divergent PD-related mutations can generate comparable brain region specific pathologies. This indicates that some intrinsic region-specificity respecting differential neuron vulnerability exists, which codetermines the disease progression. To gain insight into the pathomechanism of PD, we investigated protein expression and protein oxidation patterns of three different brain regions in a PD mouse model, the PINK1 knockout mice (PINK1-KO), in comparison to wild type control mice. The dysfunction of PINK1 presumably affects mitochondrial turnover by disturbing mitochondrial autophagic pathways. The three brain regions investigated are the midbrain, which is the location of substantia nigra; striatum, the major efferent region of substantia nigra; and cerebral cortex, which is more distal to PD pathology. In all three regions, mitochondrial proteins responsible for energy metabolism and membrane potential were significantly altered in the PINK1-KO mice, but with very different region specific accents in terms of up/down-regulations. This suggests that disturbed mitophagy presumably induced by PINK1 knockout has heterogeneous impacts on different brain regions. Specifically, the midbrain tissue seems to be most severely hit by defective mitochondrial turnover, whereas cortex and striatum could compensate for mitophagy nonfunction by feedback stimulation of other catabolic programs. In addition, cerebral cortex tissues showed the mildest level of protein oxidation in both PINK1-KO and wild type mice, indicating either a better oxidative protection or less reactive oxygen species (ROS) pressure in this brain region. Ultra-structural histological examination in normal mouse brain revealed higher incidences of mitophagy vacuoles in cerebral cortex than in striatum and substantia nigra. Taken together, the delicate balance between oxidative protection and mitophagy capacity in different brain regions could contribute to brain region-specific pathological patterns in PD.