OBJECTIVE Neuroinflammation plays a critical role in neurodegenerative disorders,although the inflammation may not the initiating factor.Parkinson disease(PD)is characterized pathologically by the accumulation of alph...OBJECTIVE Neuroinflammation plays a critical role in neurodegenerative disorders,although the inflammation may not the initiating factor.Parkinson disease(PD)is characterized pathologically by the accumulation of alpha synuclein(α-syn)and the loss of the dopamine(DA)neurons in the substantia nigra(SN),which has been reported to be induced by the stereotaxic injection of lipopolysaccharide(LPS)to the SN region in rodents.This study is to investigate the therapeutic benefit of the inhibition of miR-873 in PD.METHODS Rats received the right-unilaterally injection with concentrated LV-sponge or LV-EGFP 3 d before LPS treatment,7 or 14 d after LPS treatment.The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 21 d after LPS injection.The regulation of miR-873 on the genes related with cholesterol transport and inflammation was assayed in SH-SY5Y cells and U251 cells.RESULTS TLR4-My D88 signaling pathway was involved the regulation of miR-873 by LPS.The luciferase assay showed that HMGCR,ABCA1 and A20 were down-stream genes of miR-873.The transfection of miR-873 decreased the cholesterol levels in cell membrane,but increased in lysosome in SH-SY5Y cells.Compared with the control SH-SY5Y cells,cholesterol levels were higher in lysosome withα-synuclein overexpression or LPS treatment.The transfection of miR-873 increased theα-syn levels in lysosome in cel s withα-synuclein overexpression.The loss of dopaminergic neuorns induced by LPS was significantly respectively decreased by 22.8%,35.6%and 57% after the inhibition of miR-873 at 3 d before LPS treatment,7 or14 d after LPS treatment.Compared with LPS-treated group,the number of the rotation of rats was decreased by 60.4%,33.5%and 13.2%after the inhibition of miR-873 at 3 d before LPS treatment,7or 14 d after LPS treatment.The inhibition of miR-873 significantly decreased accumulation ofα-syn.The m RNA levels of HMGCR,ABCA1 and A20 in SN were decreased by LPS treatment,which was attenuated by the injection of LV-sponge.CONCLUSION The selective regulation of miR-873 can protect the dopaminergic neurons from the LPS-induced damage.The inhibition of miR-873 can attenuate the relocation of cholesterol in lysosome and the accumulation ofα-syn in neurons induced by LPS via the regulation of HMGCR,ABCA1 and A20.展开更多
基金supported by National Natural Science Foundation of China(1673503)
文摘OBJECTIVE Neuroinflammation plays a critical role in neurodegenerative disorders,although the inflammation may not the initiating factor.Parkinson disease(PD)is characterized pathologically by the accumulation of alpha synuclein(α-syn)and the loss of the dopamine(DA)neurons in the substantia nigra(SN),which has been reported to be induced by the stereotaxic injection of lipopolysaccharide(LPS)to the SN region in rodents.This study is to investigate the therapeutic benefit of the inhibition of miR-873 in PD.METHODS Rats received the right-unilaterally injection with concentrated LV-sponge or LV-EGFP 3 d before LPS treatment,7 or 14 d after LPS treatment.The animals were tested for rotational behavior with the dopaminergic agonist apomorphine dissolved in sterile saline at 21 d after LPS injection.The regulation of miR-873 on the genes related with cholesterol transport and inflammation was assayed in SH-SY5Y cells and U251 cells.RESULTS TLR4-My D88 signaling pathway was involved the regulation of miR-873 by LPS.The luciferase assay showed that HMGCR,ABCA1 and A20 were down-stream genes of miR-873.The transfection of miR-873 decreased the cholesterol levels in cell membrane,but increased in lysosome in SH-SY5Y cells.Compared with the control SH-SY5Y cells,cholesterol levels were higher in lysosome withα-synuclein overexpression or LPS treatment.The transfection of miR-873 increased theα-syn levels in lysosome in cel s withα-synuclein overexpression.The loss of dopaminergic neuorns induced by LPS was significantly respectively decreased by 22.8%,35.6%and 57% after the inhibition of miR-873 at 3 d before LPS treatment,7 or14 d after LPS treatment.Compared with LPS-treated group,the number of the rotation of rats was decreased by 60.4%,33.5%and 13.2%after the inhibition of miR-873 at 3 d before LPS treatment,7or 14 d after LPS treatment.The inhibition of miR-873 significantly decreased accumulation ofα-syn.The m RNA levels of HMGCR,ABCA1 and A20 in SN were decreased by LPS treatment,which was attenuated by the injection of LV-sponge.CONCLUSION The selective regulation of miR-873 can protect the dopaminergic neurons from the LPS-induced damage.The inhibition of miR-873 can attenuate the relocation of cholesterol in lysosome and the accumulation ofα-syn in neurons induced by LPS via the regulation of HMGCR,ABCA1 and A20.
