Li Gehui, Luo Wanxian, Wang Baoyan, Qian Chen, Ye Yongyi, Li Yuantao, Zhang Shizhong
Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The National Key Clinical Specialty, Department of Neurosurgery, The Engineering Technology Research Center of Education Ministry of China, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Department of Anesthesiology, Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China.
Front Cell Neurosci. 2021 Jan 18;14:620020. doi: 10.3389/fncel.2020.620020. eCollection 2020.
Autophagy dysfunction has been directly linked with the onset and progression of Parkinson's disease (PD), but the underlying mechanisms are not well understood. High-mobility group A1 (HMGA1), well-known chromatin remodeling proteins, play pivotal roles in diverse biological processes and diseases. Their function in neural cell death in PD, however, have not yet been fully elucidated. Here, we report that HMGA1 is highly induced during dopaminergic cell death and mice models of PD . Functional studies using genetic knockdown of endogenous HMGA1 show that HMGA1 signaling inhibition accelerates neural cell death, at least partially through aggravating MPP-induced autophagic flux reduction resulting from partial block in autophagic flux at the terminal stages, indicating a novel potential neuroprotective role for HMGA1 in dopaminergic neurons death. MicroRNA-103/107 (miR-103/107) family, which is highly expressed in neuron, coordinately ensures proper end-stage autophagy. We further illustrate that MPP/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced HMGA1 elevation counterparts the effect of miR-103/107 downregulation by directly binding to their promoters, respectively, sustaining their expression in MPP-damaged MN9D cells and modulates autophagy through CDK5R1/CDK5 signaling pathway. We also find that HMGA1 is a direct target of miR-103/107 family. Thus, our results suggest that HMGA1 forms a negative feedback loop with miR-103/107-CDK5R1/CDK5 signaling to regulate the MPP/MPTP-induced autophagy impairment and neural cell death. Collectively, we identify a paradigm for compensatory neuroprotective HMGA1 signaling in dopaminergic neurons that could have important therapeutic implications for PD.
自噬功能障碍与帕金森病（PD）的发生和发展直接相关，但其潜在机制尚未完全明确。高迁移率族蛋白A1（HMGA1）是著名的染色质重塑蛋白，在多种生物学过程和疾病中发挥关键作用。然而，它们在PD神经细胞死亡中的功能尚未完全阐明。在此，我们报告HMGA1在多巴胺能细胞死亡和PD小鼠模型中被高度诱导。使用内源性HMGA1基因敲低的功能研究表明，HMGA1信号抑制会加速神经细胞死亡，至少部分是通过加重MPP诱导的自噬流减少，这是由于自噬流在终末阶段部分受阻所致，表明HMGA1在多巴胺能神经元死亡中具有新的潜在神经保护作用。微小RNA-103/107（miR-103/107）家族在神经元中高度表达，共同确保自噬终末阶段的正常进行。我们进一步阐明，MPP/1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）诱导的HMGA1升高分别通过直接结合miR-103/107的启动子，抵消了miR-103/107下调的影响，维持其在MPP损伤的MN9D细胞中的表达，并通过CDK5R1/CDK5信号通路调节自噬。我们还发现HMGA1是miR-103/107家族的直接靶点。因此，我们的结果表明，HMGA1与miR-103/107-CDK5R1/CDK5信号形成负反馈环，以调节MPP/MPTP诱导的自噬损伤和神经细胞死亡。总体而言，我们确定了多巴胺能神经元中补偿性神经保护HMGA1信号的模式，这可能对PD具有重要的治疗意义。
