Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the selective degeneration of dopaminergic neurons in the substantia nigra pars compacta resulting in an irreversible and a debilitating motor dysfunction. Though both genetic and idiopathic factors are implicated in the disease etiology, idiopathic PD comprise the majority of clinical cases and is caused by exposure to environmental toxicants and oxidative stress. Fyn kinase activation has been identified as an early molecular signaling event that primes neuroinflammatory and neurodegenerative events associated with dopaminergic cell death. However, the upstream regulator of Fyn activation remains unidentified. We investigated whether the lipid and tyrosine phosphatase PTEN (Phosphatase and Tensin homolog deleted on chromosome 10) could be the upstream regulator of Fyn activation in PD models as PTEN has been previously reported to contribute to Parkinsonian pathology. Our findings, using bioluminescence resonance energy transfer (BRET) and immunoblotting, indicate for the first time that PTEN is a critical early stress sensor in response to oxidative stress and neurotoxicants in in vitro models of PD. Pharmacological attenuation of PTEN activity rescues dopaminergic neurons from neurotoxicant-induced cytotoxicity by modulating Fyn kinase activation. Our findings also identify PTEN’s novel roles in contributing to mitochondrial dysfunction which contribute to neurodegenerative processes. Interestingly, we found that PTEN positively regulates interleukin-1β (IL-1β) and the transcription of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Taken together, we have identified PTEN as a disease course altering pharmacological target that may be further validated for the development of novel therapeutic strategies targeting PD.

Graphical Abstract

中文翻译：

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PTEN 的药理抑制通过减弱细胞凋亡和神经炎症信号事件来拯救多巴胺能神经元

帕金森病 (PD) 是一种进行性神经退行性疾病，其特征是黑质致密部的多巴胺能神经元选择性变性，导致不可逆且衰弱的运动功能障碍。尽管遗传和特发性因素都与疾病病因有关，但特发性 PD 占临床病例的大多数，并且是由暴露于环境毒物和氧化应激引起的。Fyn 激酶激活已被确定为一种早期分子信号传导事件，可引发与多巴胺能细胞死亡相关的神经炎症和神经退行性事件。然而，Fyn 激活的上游调节因子仍不清楚。我们研究了脂质和酪氨酸磷酸酶 PTEN（10 号染色体上删除的磷酸酶和张力蛋白同源物）是否可能是 PD 模型中 Fyn 激活的上游调节因子，因为之前有报道称 PTEN 与帕金森病病理学有关。我们使用生物发光共振能量转移 (BRET) 和免疫印迹的研究结果首次表明，PTEN 是体外 PD 模型中响应氧化应激和神经毒物的关键早期应激传感器。PTEN 活性的药理学减弱通过调节 Fyn 激酶激活来拯救多巴胺能神经元免受神经毒剂诱导的细胞毒性。我们的研究结果还确定了 PTEN 在导致线粒体功能障碍（导致神经退行性过程）方面的新作用。有趣的是，我们发现 PTEN 正向调节白细胞介素 1β (IL-1β) 和活化 B 细胞核因子 kappa 轻链增强子 (NF-κB) 的转录。综上所述，我们已将 PTEN 确定为改变病程的药理学靶点，可进一步验证其用于开发针对 PD 的新型治疗策略。

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