BackgroundParkinson's disease (PD) is a well-known neurodegenerative disease that is usually caused by the progressive loss of dopamine neurons and the formation of Lewy vesicles. 3,4-Methylenedioxymethamphetamine (MDMA) has been reported to cause damage to human substantia nigra neurons and an increased risk of PD, but the exact molecular mechanisms need further investigation.MethodsMPTP- and MPP+-induced PD cells and animal models were treated with Nissl staining to assess neuronal damage in the substantia nigra (SN) area; immunohistochemistry to detect TH expression in the SN; TUNEL staining to detect apoptosis in the SN area; Western blotting to detect the inflammatory factors NF-& kappa;B, TNF-& alpha;, IL-6 and mitogen-activated protein kinase kinase kinase 3 (MEKK3); Griess assay for NO; RT-qPCR for metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and miR-124 expression; Cell proliferation was assessed by CCK-8. Dual luciferase reporter genes were used to verify targeting relationships.ResultsMDMA promoted MALAT1 expression, and knockdown of MALAT1 alleviated the MDMA-induced inhibition of SH-SY5Y cell proliferation, inflammation, NO release, SN neuronal injury, and TH expression inhibition. Both inhibition of miR-124 and overexpression of MEKK3 reversed the neuroprotective effects exhibited by knockdown of MALAT1.ConclusionMDMA promotes MALAT1 expression and inhibits the targeted downregulation of MEKK3 by miR-124, resulting in upregulation of the expression of MEKK3 and finally jointly promoting PD progression.
基金:
This research was supported by Geng Xin, a Project for the Training of Technological Innovation Talents in Yunnan Province (202205AD160006), Associated Project of Yunnan Province Science & Technology Department and Kunming Medical University Basic Research for Application (202301AY070001-209). a subproject of the Special Fund for Applied Basic Research of The Center for Diagnosis and Treatment of Neurological Diseases in Yunnan Province (ZX2019- 03-05), The Major Science and Technology Special Project of Yunnan Province (202102AA100061). PhD Research Fund of the First Affiliated Hospital of Kunming Medical University (2020BS019), and PhD Research Fund of the First Affiliated Hospital of Kunming Medical University (2022BS015).