通过 parkin 对 PARIS 和 PGC-1α 的调节促进线粒体生物发生，作为迷迭香酸神经保护作用的机制。
Promotion of mitochondrial biogenesis via the regulation of PARIS and PGC-1α by parkin as a mechanism of neuroprotection by carnosic acid.
机构信息
Department of Nutrition, China Medical University, Taichung, Taiwan.
Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan; Translational Medicine Research Center, China Medical University Hospital, Taichung, Taiwan.
出版信息
Phytomedicine. 2021 Jan;80:153369. doi: 10.1016/j.phymed.2020.153369. Epub 2020 Oct 8.
BACKGROUND
Impairment of mitochondrial biogenesis is associated with the pathological progression of Parkinson's disease (PD). Parkin-interacting substrate (PARIS) can be ubiquitinated by parkin and prevents the repression of proliferator-activated receptor gamma coactivator-1-alpha (PGC-1α).
PURPOSE
This study investigated whether the neuroprotective mechanism of carnosic acid (CA) from rosemary is mediated via the regulation of PARIS and PGC-1α by parkin.
METHODS
The Western blotting and RT-PCR were used to determine protein and mRNA, respectively. To investigate the protein-protein interaction of between PARIS and ubiquitin, the immunoprecipitation assay (IP assay) was utilized. Silencing of endogenous parkin or PGC-1α was performed by using transient transfection of small interfering RNA (siRNA).
RESULTS
SH-SY5Y cells treated with 6-hydroxydopamine (6-OHDA) increased PARIS protein, decreased PGC-1α protein, and reduced protein and mRNA of mitochondrial biogenesis-related genes. CA pretreatment reversed the effects of 6-OHDA. By IP assay, the interaction of PARIS with ubiquitin protein caused by CA was stronger than that caused by 6-OHDA. Moreover, knockdown of parkin attenuated the ability of CA to reverse the 6-OHDA-induced increase in PARIS and decrease in PGC-1α expression. PGC-1α siRNA was used to investigate how CA influenced the effect of 6-OHDA on the modulation of mitochondrial biogenesis and apoptosis. In the presence of PGC-1α siRNA, CA could no longer significantly reverse the reduction of mitochondrial biogenesis or the induction of cleavage of apoptotic-related proteins by 6-OHDA.
CONCLUSION
The cytoprotective of CA is related to the enhancement of mitochondrial biogenesis by inhibiting PARIS and inducing PGC-1α by parkin. The activation of PGC-1α-mediated mitochondrial biogenesis by CA prevents the degeneration of dopaminergic neurons, CA may have therapeutic application in PD.
背景
线粒体生物发生的损伤与帕金森病（PD）的病理进展有关。Parkin 相互作用底物（PARIS）可被 Parkin 泛素化，并防止增殖物激活受体γ共激活因子-1-α（PGC-1α）的抑制。
目的
本研究探讨迷迭香酸（CA）的神经保护机制是否通过 Parkin 调节 PARIS 和 PGC-1α来介导。
方法
采用 Western blot 和 RT-PCR 分别检测蛋白和 mRNA。为了研究 PARIS 和泛素之间的蛋白-蛋白相互作用，采用免疫沉淀（IP）assay。通过瞬时转染小干扰 RNA（siRNA）来沉默内源性 Parkin 或 PGC-1α。
结果
用 6-羟多巴胺（6-OHDA）处理的 SH-SY5Y 细胞增加了 PARIS 蛋白，降低了 PGC-1α 蛋白，并减少了线粒体生物发生相关基因的蛋白和 mRNA。CA 预处理逆转了 6-OHDA 的作用。通过 IP assay，CA 引起的 PARIS 与泛素蛋白的相互作用强于 6-OHDA 引起的相互作用。此外，Parkin 的敲低减弱了 CA 逆转 6-OHDA 诱导的 PARIS 增加和 PGC-1α 表达减少的能力。用 PGC-1α siRNA 来研究 CA 如何影响 6-OHDA 对线粒体生物发生和凋亡调节的影响。在存在 PGC-1α siRNA 的情况下，CA 不再能显著逆转 6-OHDA 引起的线粒体生物发生减少或诱导凋亡相关蛋白的切割。
结论
CA 的细胞保护作用与通过抑制 PARIS 和诱导 Parkin 介导的 PGC-1α有关。CA 激活 PGC-1α 介导的线粒体生物发生可防止多巴胺能神经元的退化，CA 可能在 PD 中有治疗应用。
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