Department of Neurology, Baotou Central Hospital, Baotou, 014040, Inner Mongolia, People's Republic of China.
Department of Neurology, The Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou Workers Hospital, Liuzhou, 545005, Guangxi, People's Republic of China.
Funct Integr Genomics. 2024 Sep 17;24(5):161. doi: 10.1007/s10142-024-01446-4.
Epigenetic regulation plays a role in Parkinson's disease (PD), and ten-eleven translocation methylcytosine dioxygenase 1 (TET1) catalyzes the first step in DNA demethylation by converting 5-methylcytosine to 5-hydroxymethylcytosine. We investigated whether TET1 binds to the promoter of the transient receptor potential cation channel subfamily V member 1 (TRPV1) and regulates its expression, thereby controlling oxidative stress in PD. TRPV1 was identified as an oxidative stress-associated gene in the GSE20186 dataset including substantia nigra from 14 patients with PD and 14 healthy controls and the Genecards database. Lentiviral vectors were used to manipulate Trpv1 expression in rats, followed by 6-hydroxydopamine hydrochloride (6-OHDA) injection for modeling. Behavioral tests, immunofluorescence, Nissl staining, western blot assays, DHE fluorescent probe, biochemical analysis, and ELISA were conducted to assess oxidative stress and neurotoxicity. Trpv1 expression was significantly reduced in the brain tissues of 6-OHDA-treated Parkinsonian rats. Trpv1 alleviated behavioral dysfunction, oxidative stress, and dopamine neuron loss in rats. TET1 mediated TRPV1 hydroxymethylation to promote its expression, and Trpv1 inhibition reversed the mitigating effect of Tet1 on oxidative stress and behavioral dysfunction in PD. TRPV1 activated the AMPK signaling by promoting AMPK phosphorylation to alleviate neurotoxicity and oxidative stress in SH-SY5Y cells. Tet1-mediated Trpv1 hydroxymethylation modification promotes the Ampk signaling activation, thereby eliciting neuroprotection in 6-OHDA-treated Parkinsonian rats. These findings provide experimental evidence that targeting the TET1/TRPV1 axis may be neuroprotective for PD by acting on the AMPK signaling.
表观遗传调控在帕金森病（PD）中发挥作用，而 ten-eleven translocation methylcytosine dioxygenase 1（TET1）通过将 5-甲基胞嘧啶转化为 5-羟甲基胞嘧啶来催化 DNA 去甲基化的第一步，从而催化 DNA 去甲基化。我们研究了 TET1 是否与瞬时受体电位阳离子通道亚家族 V 成员 1（TRPV1）的启动子结合并调节其表达，从而控制 PD 中的氧化应激。TRPV1 被鉴定为 GSE20186 数据集（包括来自 14 名 PD 患者和 14 名健康对照者的黑质）和 Genecards 数据库中与氧化应激相关的基因。慢病毒载体用于操纵大鼠中的 Trpv1 表达，然后用 6-羟多巴胺盐酸盐（6-OHDA）注射进行建模。行为测试、免疫荧光、尼氏染色、western blot 测定、DHE 荧光探针、生化分析和 ELISA 用于评估氧化应激和神经毒性。6-OHDA 处理的帕金森大鼠脑组织中 Trpv1 表达明显降低。Trpv1 减轻了大鼠的行为功能障碍、氧化应激和多巴胺神经元丢失。TET1 介导 TRPV1 羟甲基化以促进其表达，Trpv1 抑制逆转了 Tet1 对 PD 中氧化应激和行为功能障碍的缓解作用。TRPV1 通过促进 AMPK 磷酸化激活 AMPK 信号，从而减轻 SH-SY5Y 细胞的神经毒性和氧化应激。Tet1 介导的 Trpv1 羟甲基化修饰促进 Ampk 信号的激活，从而在 6-OHDA 处理的帕金森大鼠中引起神经保护作用。这些发现提供了实验证据，表明靶向 TET1/TRPV1 轴可能通过作用于 AMPK 信号对 PD 具有神经保护作用。
