Background and Purpose. Alterations in cholesterol homeostasis have been reported in cell and animal models of Parkinson’s disease (PD), although there are inconsistent data about the association between serum cholesterol levels and risk of PD. Here, we investigated the effects of miR-873 on lysosomal cholesterol homeostasis and progressive dopaminergic neuron damage in a lipopolysaccharide-(LPS) induced model of PD. Experimental Approach. To evaluate the therapeutic benefit of the miR-873 sponge, rats were injected with a LV-miR-873 sponge or the control vector 3 days before the right-unilateral injection of LPS into the substantia nigra (SN) pars compacta, or 8 and 16 days after LPS injection. Normal SH-SY5Y cells or SH-SY5Y cells overexpressing α-synuclein were used to evaluate the distribution of α-synuclein and cholesterol in lysosomes and to assess the autophagic flux after miR-873 transfection or ABCA1 silencing. The inhibition of miR-873 significantly ameliorated the LPS-induced accumulation of α-synuclein and loss of dopaminergic neurons in the SN at the early stage. miR-873 mediated the inhibition of ABCA1 by LPS. miR-873 transfection or ABCA1 silencing increased the lysosomal cholesterol and α-synuclein levels, and decreased the autophagic flux. The knockdown of ABCA1 or A20, which are the downstream target genes of miR-873, exacerbated the damage to LPS-induced dopaminergic neurons. Conclusion and Implications. The results suggest that the inhibition of miR-873 may play a dual protective role by improving intracellular cholesterol homeostasis and neuroinflammation in PD. The therapeutic effects of the miR-873 sponge in PD may be due to the upregulation of ABCA1 and A20.

中文翻译：

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miR-873的抑制作用在脂多糖诱导的帕金森氏病神经炎模型中提供治疗效果。

背景和目的。在帕金森氏病（PD）的细胞和动物模型中，胆固醇稳态的变化已有报道，尽管血清胆固醇水平与PD风险之间的关联性数据不一致。在这里，我们调查了脂多糖-（LPS）诱导的PD模型中miR-873对溶酶体胆固醇稳态和进行性多巴胺能神经元损害的影响。实验方法。为了评估miR-873海绵的治疗效果，在将LPS右单侧注射入黑质致密性黑实症（SN）的第8天和第8天，分别向大鼠注射LV-miR-873海绵或对照载体。 LPS注射后16天。正常的SH-SY5Y细胞或过表达α的SH-SY5Y细胞-突触核蛋白用于评估溶酶体中α-突触核蛋白和胆固醇的分布，并评估miR-873转染或ABCA1沉默后的自噬通量。在早期，miR-873的抑制作用显着改善了LPS诱导的SN中α-突触核蛋白的积累和多巴胺能神经元的丢失。miR-873介导LPS抑制ABCA1。miR-873转染或ABCA1沉默可增加溶酶体胆固醇和α-突触核蛋白水平，并降低自噬通量。miR-873的下游靶基因ABCA1或A20的敲低加剧了LPS诱导的多巴胺能神经元的损伤。结论与启示。结果表明，miR-873的抑制作用可能通过改善PD中的细胞内胆固醇稳态和神经炎症而起双重保护作用。miR-873海绵在PD中的治疗作用可能归因于ABCA1和A20的上调。