MDMA targets miR-124/MEKK3 via MALAT1 to promote Parkinson’s disease progression

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Abstract
Background: Parkinson’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. Methods: MPTP- 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-κB, TNF-α, 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. Results: MDMA 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. Conclusion: MDMA 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.
Funding Information
  • Yunnan Provincial High-level Health and Family Planning Technical Talent Training Fund supports the Yunnan Provincial Health Commission’s Medical Reserve Talent Training Program (H-2018054)
  • Geng Xin, a Project for the Training of Technological Innovation Talents in Yunnan Province (202205AD160006)
  • sub-project 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 Aiffliated Hospital of Kunming Medical University (2020BS019)

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