Thioredoxin-interacting protein induced -synuclein accumulation via inhibition of autophagic flux: Implications for Parkinson's disease
Thioredoxin-interacting protein induced -synuclein accumulation via inhibition of autophagic flux: Implications for Parkinson's disease
复制标题
硫氧还蛋白相互作用蛋白通过抑制自噬通量诱导突触核蛋白积累：对帕金森病的影响
DOI：
10.1111/cns.12721
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发表时间：
2017-09-01
影响因子：
5.5
通讯作者：
Yu, Yun-Li
中科院分区：
文献类型：
--
作者：
Su, Cun-Jin;Feng, Yu;Yu, Yun-Li
目的硫氧还蛋白相互作用蛋白 (TXNIP) 通过抑制硫氧还蛋白 (Trx) 与氧化应激的激活相关。然而，一些证据指出，TXNIP 在信号复合物中充当支架蛋白，独立于细胞氧化还原调节。自噬-溶酶体途径在清除错误折叠的蛋白质和功能失调的细胞器中发挥着重要作用。溶酶体功能障碍与多种神经退行性疾病有关，包括帕金森病（PD）。尽管有研究人员报道TXNIP抑制自噬流，但其具体机制却很少研究。方法本研究通过Western blot法研究TXNIP对转染TXNIP质粒的HEK293细胞自噬流和β-突触核蛋白积累的影响。进一步，我们通过IHC探讨了TXNIP对黑质DA神经元存活的影响。结果我们发现TXNIP诱导LC3-II表达，但未能降解自噬底物p62。此外，TXNIP 加剧了 α-突触核蛋白的积累。我们还发现 TXNIP 抑制溶酶体膜蛋白 ATP13A2 的表达。此外，我们发现 ATP13A2 的过度表达减弱了 TXNIP 诱导的自噬流和 β-突触核蛋白积累的损害。此外，TXNIP在黑质中的过度表达导致DA神经元丢失。结论我们的数据表明TXNIP通过抑制ATP13A2阻断自噬流并诱导β-突触核蛋白积累，表明TXNIP是PD中的致病蛋白。
AimsThioredoxin-interacting protein (TXNIP) is associated with activation of oxidative stress through inhibition of thioredoxin (Trx). However, some evidences point out that TXNIP acts as a scaffolding protein in signaling complex independent of cellular redox regulation. The autophagy-lysosomal pathway plays important roles in the clearance of misfolded proteins and dysfunctional organelles. Lysosomal dysfunction has been involved in several neurodegenerative disorders including Parkinson's disease (PD). Although researchers have reported that TXNIP inhibited autophagic flux, the specific mechanism is rarely studied.MethodsIn this study, we investigated the effects of TXNIP on autophagic flux and -synuclein accumulation by Western blot in HEK293 cells transfected with TXNIP plasmid. Further, we explored the influence of TXNIP on DA neuron survival in substantia nigra by IHC.ResultsWe found that TXNIP induced LC3-II expression, but failed to degrade p62, a substrate of autophagy. Also, TXNIP aggravated -synuclein accumulation. We also found that TXNIP inhibited the expression of ATP13A2, a lysosomal membrane protein. Moreover, we found that overexpression of ATP13A2 attenuated the impairment of autophagic flux and -synuclein accumulation induced by TXNIP. Furthermore, overexpression of TXNIP in substantia nigra resulted in loss of DA neuron.ConclusionOur data suggested that TXNIP blocked autophagic flux and induced -synuclein accumulation through inhibition of ATP13A2, indicating TXNIP was adisease-causing protein in PD.