NADPH oxidase promotes Parkinsonian phenotypes by impairing autophagic flux in an mTORC1-independent fashion in a cellular model of Parkinson's disease.
NADPH oxidase promotes Parkinsonian phenotypes by impairing autophagic flux in an mTORC1-independent fashion in a cellular model of Parkinson's disease.
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DOI：
10.1038/srep22866
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发表时间：
2016-03-10
影响因子：
4.6
通讯作者：
Rodney GG
中科院分区：
文献类型：
--
作者：
Pal R;Bajaj L;Sharma J;Palmieri M;Di Ronza A;Lotfi P;Chaudhury A;Neilson J;Sardiello M;Rodney GG
氧化应激和胞质中错误折叠蛋白的异常积累是与帕金森病（PD）相关的关键病理特征。NADPH氧化酶（Nox 2）在PD的发病机制中上调;然而，Nox 2介导的氧化应激在PD发病机制中的潜在机制仍然未知。使用鱼藤酮诱导的PD细胞模型，我们观察到短时间暴露于鱼藤酮（0.5 μM）通过激活Nox 2依赖性Src/PI 3 K/Akt轴导致自噬通量受损，从而破坏Beclin 1-VPS 34相互作用，而该相互作用不依赖于mTORC 1活性。持续暴露于较高剂量（10 μM）的鱼藤酮可降低mTORC 1活性;然而，由于溶酶体活性失调以及随后诱导的凋亡机制，自噬通量仍然受损。累积起来，我们的研究结果强调了PD的复杂致病机制，其中短期和长期氧化应激改变了不同的信号通路，最终导致异常的自噬活性和疾病表型。Nox 2依赖性氧化应激的抑制减弱了受损的自噬和细胞死亡，突出了这些途径治疗PD患者的重要性和治疗潜力。
Oxidative stress and aberrant accumulation of misfolded proteins in the cytosol are key pathological features associated with Parkinson’s disease (PD). NADPH oxidase (Nox2) is upregulated in the pathogenesis of PD; however, the underlying mechanism(s) of Nox2-mediated oxidative stress in PD pathogenesis are still unknown. Using a rotenone-inducible cellular model of PD, we observed that a short exposure to rotenone (0.5 μM) resulted in impaired autophagic flux through activation of a Nox2 dependent Src/PI3K/Akt axis, with a consequent disruption of a Beclin1-VPS34 interaction that was independent of mTORC1 activity. Sustained exposure to rotenone at a higher dose (10 μM) decreased mTORC1 activity; however, autophagic flux was still impaired due to dysregulation of lysosomal activity with subsequent induction of the apoptotic machinery. Cumulatively, our results highlight a complex pathogenic mechanism for PD where short- and long-term oxidative stress alters different signaling pathways, ultimately resulting in anomalous autophagic activity and disease phenotype. Inhibition of Nox2-dependent oxidative stress attenuated the impaired autophagy and cell death, highlighting the importance and therapeutic potential of these pathways for treating patients with PD.