PMID- 37688681 OWN - NLM STAT- MEDLINE DCOM- 20231110 LR - 20240208 IS - 1573-4978 (Electronic) IS - 0301-4851 (Print) IS - 0301-4851 (Linking) VI - 50 IP - 11 DP - 2023 Nov TI - MDMA targets miR-124/MEKK3 via MALAT1 to promote Parkinson's disease progression. PG - 8889-8899 LID - 10.1007/s11033-023-08775-w [doi] AB - 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-kappaB, 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. 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. CI - (c) 2023. The Author(s). FAU - Geng, Xin AU - Geng X AD - The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China. AD - Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China. FAU - Li, Shipeng AU - Li S AD - The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China. AD - Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China. FAU - Li, Jinghui AU - Li J AD - The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China. AD - Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China. FAU - Qi, Renli AU - Qi R AD - The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China. AD - Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China. FAU - Zhong, Lianmei AU - Zhong L AD - The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China. 13888967787@163.com. AD - Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China. 13888967787@163.com. FAU - Yu, Hualin AU - Yu H AD - The Second Department of Neurosurgery, The First Affiliated Hospital of Kunming Medical University, Kunming, 650032, Yunnan, China. xuhl@ydyy.cn. AD - Yunnan Provincial Clinical Research Center for Neurological Disease, Kunming, 650032, Yunnan, China. xuhl@ydyy.cn. LA - eng GR - H-2018054/Yunnan Provincial High-level Health and Family Planning Technical Talent Training Fund supports the Yunnan Provincial Health Commission's Medical Reserve Talent Training Program/ GR - 202205AD160006/Geng Xin, a Project for the Training of Technological Innovation Talents in Yunnan Province/ GR - ZX2019-03-05/Sub-project of the Special Fund for Applied Basic Research of The Center for Diagnosis and Treatment of Neurological Diseases in Yunnan Province/ GR - 202102AA100061/The Major Science and Technology Special Project of Yunnan Province/ GR - 2020BS019/PhD Research Fund of the First Aiffliated Hospital of Kunming Medical University/ PT - Journal Article DEP - 20230909 PL - Netherlands TA - Mol Biol Rep JT - Molecular biology reports JID - 0403234 RN - KE1SEN21RM (N-Methyl-3,4-methylenedioxyamphetamine) RN - 0 (RNA, Long Noncoding) RN - 0 (MicroRNAs) RN - 0 (MIRN124 microRNA, human) SB - IM MH - Animals MH - Humans MH - *Parkinson Disease/genetics MH - *N-Methyl-3,4-methylenedioxyamphetamine/pharmacology MH - *RNA, Long Noncoding/genetics/metabolism MH - *Neurodegenerative Diseases MH - *Neuroblastoma MH - *MicroRNAs/metabolism MH - Apoptosis MH - Dopaminergic Neurons/metabolism MH - Disease Progression MH - Cell Line, Tumor PMC - PMC10635915 OTO - NOTNLM OT - MALAT1 OT - MDMA OT - MEKK3 OT - Neuronal damage OT - Parkinson's disease OT - miR-124 COIS- The authors have no conflicts of interest to declare. EDAT- 2023/09/09 21:42 MHDA- 2023/11/10 06:45 PMCR- 2023/09/09 CRDT- 2023/09/09 11:08 PHST- 2023/07/10 00:00 [received] PHST- 2023/08/21 00:00 [accepted] PHST- 2023/11/10 06:45 [medline] PHST- 2023/09/09 21:42 [pubmed] PHST- 2023/09/09 11:08 [entrez] PHST- 2023/09/09 00:00 [pmc-release] AID - 10.1007/s11033-023-08775-w [pii] AID - 8775 [pii] AID - 10.1007/s11033-023-08775-w [doi] PST - ppublish SO - Mol Biol Rep. 2023 Nov;50(11):8889-8899. doi: 10.1007/s11033-023-08775-w. Epub 2023 Sep 9.