Department of Clinical Neuroscience, Institute of Neurology, University College London, London, UK.
Cell Death Dis. 2013 Mar 14;4(3):e545. doi: 10.1038/cddis.2013.73.
The presence of α-synuclein aggregates in the characteristic Lewy body pathology seen in idiopathic Parkinson's disease (PD), together with α-synuclein gene mutations in familial PD, places α-synuclein at the center of PD pathogenesis. Decreased levels of the chaperone-mediated autophagy (CMA) proteins LAMP-2A and hsc70 in PD brain samples suggests compromised α-synuclein degradation by CMA may underpin the Lewy body pathology. Decreased CMA protein levels were not secondary to the various pathological changes associated with PD, including mitochondrial respiratory chain dysfunction, increased oxidative stress and proteasomal inhibition. However, decreased hsc70 and LAMP-2A protein levels in PD brains were associated with decreases in their respective mRNA levels. MicroRNA (miRNA) deregulation has been reported in PD brains and we have identified eight miRNAs predicted to regulate LAMP-2A or hsc70 expression that were reported to be increased in PD. Using a luciferase reporter assay in SH-SY5Y cells, four and three of these miRNAs significantly decreased luciferase activity expressed upstream of the lamp-2a and hsc70 3'UTR sequences respectively. We confirmed that transfection of these miRNAs also decreased endogenous LAMP-2A and hsc70 protein levels respectively and resulted in significant α-synuclein accumulation. The analysis of PD brains confirmed that six and two of these miRNAs were significantly increased in substantia nigra compacta and amygdala respectively. These data support the hypothesis that decreased CMA caused by miRNA-induced downregulation of CMA proteins plays an important role in the α-synuclein pathology associated with PD, and opens up a new avenue to investigate PD pathogenesis.
α-突触核蛋白在特发性帕金森病（PD）中所见的特征性路易体病理中的聚集，以及 PD 家族性中的α-突触核蛋白基因突变，使α-突触核蛋白处于 PD 发病机制的中心。PD 脑样本中伴侣介导的自噬（CMA）蛋白 LAMP-2A 和 hsc70 的水平降低表明，CMA 介导的α-突触核蛋白降解受损可能是路易体病理的基础。CMA 蛋白水平降低不是与 PD 相关的各种病理变化（包括线粒体呼吸链功能障碍、氧化应激增加和蛋白酶体抑制）的次要原因。然而，PD 脑中 hsc70 和 LAMP-2A 蛋白水平的降低与它们各自的 mRNA 水平的降低有关。PD 脑中存在 microRNA（miRNA）失调的报道，我们已经确定了 8 种 miRNA，它们预测可以调节 LAMP-2A 或 hsc70 的表达，这些 miRNA 在 PD 中被报道增加。在 SH-SY5Y 细胞中使用荧光素酶报告基因检测，其中 4 种和 3 种 miRNA 分别显著降低了 lamp-2a 和 hsc70 3'UTR 序列上游表达的荧光素酶活性。我们证实，这些 miRNA 的转染也分别降低了内源性 LAMP-2A 和 hsc70 蛋白水平，并导致显著的α-突触核蛋白积累。对 PD 脑的分析证实，其中 6 种和 2 种 miRNA 在黑质致密部和杏仁核中分别显著增加。这些数据支持这样一种假设，即 miRNA 诱导的 CMA 蛋白下调导致 CMA 降低，这在与 PD 相关的α-突触核蛋白病理中起着重要作用，并为研究 PD 发病机制开辟了新途径。
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