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 in vitro and mice models of PD in vivo. 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氏病（PD）的发作和发展直接相关，但其潜在机制尚不十分清楚。高迁移率的A1组（HMGA1）是众所周知的染色质重塑蛋白，在多种生物过程和疾病中起着关键作用。然而，它们在PD中神经细胞死亡中的功能尚未完全阐明。在这里，我们报告在多巴胺能细胞死亡期间高度诱导HMGA1体外 和PD小鼠模型 体内。使用内源性HMGA1的基因敲除进行的功能研究表明，HMGA1信号抑制至少部分通过加重MPP ⁺诱导的自噬通量减少而加速了神经细胞死亡，这是由于末期自噬通量的部分阻滞所致，表明HMGA1具有新型的潜在神经保护作用在多巴胺能神经元死亡。在神经元中高表达的MicroRNA-103 / 107（miR-103 / 107）家族协调地确保了适当的末期自噬。我们进一步说明，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其启动子而对应miR-103 / 107下调的作用，保持其在MPP ^+中的表达受损的MN9D细胞并通过CDK5R1 / CDK5信号通路调节自噬。我们还发现HMGA1是miR-103 / 107家族的直接靶标。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。总的来说，我们确定了多巴胺能神经元中补偿性神经保护性HMGA1信号传导的范例，该范例可能对PD具有重要的治疗意义。