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Protective Role of Mrna Demethylase FTO on Axon Guiding Molecules of Nigro-Striatal Projection System in Manganese-Induced Parkinsonism

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Protective Role of Mrna Demethylase FTO on Axon Guiding Molecules of Nigro-Striatal Projection System in Manganese-Induced Parkinsonism Protective role of mRNA demethylase FTO on axon guiding molecules of nigro-striatal projection system in manganese-induced Parkinsonism Zhipeng Qi China Medical University Jiashuo Li China Medical University Ke Zhang China Medical University Yanan Liu China Medical University Xinxin Yang China Medical University Minghui Li China Medical University Xianchao Du China Medical University Lei Zhang China Medical University Yi Wen China Medical University Bin Xu China Medical University Wei Liu China Medical University Zhaofa Xu China Medical University Yu Deng ( [email protected] ) China Medical University https://orcid.org/0000-0003-2292-2957 Research article Keywords: Manganese, Parkinsonism, FTO, ephrin-B2, m6A, YTHDF2 Page 1/32 Posted Date: July 19th, 2021 DOI: https://doi.org/10.21203/rs.3.rs-710184/v1 License: This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 2/32 Abstract Background Parkinson's disease (PD) is a neurodegenerative disease caused by environmental and genetic factors. Manganese (Mn) exposure is a major environmental cause of PD. Cellular and molecular mechanism of Parkinsonism caused by Mn has not been explored clearly. In addition, patients with Mn-induced Parkinsonism show poor therapeutic response to levodopa. Therefore, there is need to explore the mechanisms underlying neurotoxicity of Mn exposure. Methods In short, we used SH-SY5Y cells and C57BL/6 mice to characterize Mn-induced Parkinsonism. We measured the behavioral, histological, ultrastructural and nigro-striatal projection system changes, cell viability, axon growth, and other target indicator levels, which led to the discovery of a novel mechanism of Mn-induced neurotoxicity. Results The ndings of the current study showed that inhibition of fat mass and obesity-associated protein (FTO)-mediated demethylation of N6-methyladenosine (m6A) mRNA aggravates Mn-induced motor dysfunction. Notably, FTO level is low in Mn exposure model mice and enhances occurrence of dyskinesia in mice. Over-expression of FTO reduces m6A methylation in the key axon guiding molecules of nigro-striatal projection system, including ephrin-A5 and ephrin-B2. It increases ephrin-B2 mRNA decay through the m6A reader YT521-B homology domain family proteins 2 (YTHDF2). Conclusions The ndings of this study show that FTO, a m6A demethylase, performs an indispensable function in Mn- induced Parkinsonism. Notably, re-expression of FTO and ephrin-B2 improved motor dysfunction after Mn exposure. Background Parkinson's disease (PD) is a neurodegenerative disease caused by environmental and genetic factors [1]. Approximately 3 million PD cases are reported in China, and WHO predicts that this number will increase to 5 million by 2030 [2]. Most PD cases are sporadic cases caused by environmental factors, and only less than 10% of PD cases are caused by genetic factors [3]. Manganese (Mn) exposure is one of the major environmental risk factors that cause PD [4]. Mn is a quintessential component that is important Page 3/32 for human health. It is an enzyme cofactor involved in neurotransmitter synthesis and in normal neuron and glial function [5]. Exposure to high levels of Mn can cause headache, lower limb weakness, cognitive impairment, muscle tone increase, tremor, gait diculties and other symptoms similar to those of PD. The condition is known as manganism [6], or Mn-induced Parkinsonism [7, 8]. The 2019 Report on the State of the Ecology and Environment in China reported that Mn is one of the heavy metals that exceed sanitary requirements of ingesting water [9]. China has adopted active measures, such as clean production, use of gasoline with limited Mn and elimination of Mn from drinking water. However, environmental Mn pollution is still at an excessive level due to challenges in corporate governance, poor government supervision, and insucient maintenance of equipment. In the central nervous system (CNS), excessive Mn mainly accumulates in the striatum [10, 11]. Study reports that manganism is associated with the modications of striatal dopamine (DA) pathway, which is mainly manifested by decrease in DA content [12]. However, studies on the molecular mechanisms for Mn induced dysregulation of DA levels are limited. In addition, specic mechanisms involved in motor dysfunction associated with simultaneous exposure to Mn have not been explored. Accurate establishment of neural circuits involves the axon navigating the neurons to their target [13], which is essential for DA neurons of the substantia nigra to release DA after projecting to the striatum. Studies report that axon guidance regulation of dopaminergic neurons and spinal motoneurons plays important role in brain development [14, 15]. The divergent member of the erythropoietin-producing hepatocyte receptor-interacting proteins (ephrins) mediate cell-cell communication thus regulating axon guidance and neural projection. Ephrins promotes developmental axon pathnding by modulating actin cytoskeleton dynamics [16]. Researchers report that ephrins are abundantly expressed in the striatum [17]. Sieber et al [18] reported that ephrin signaling is important in normal connectivity and function of midbrain DA neurons. The present study postulated that Mn regulation of the motor function may be associated with the function of ephrins signaling. However, the specic molecular mechanisms were not elucidated. Hundreds of RNA modications have been reported, and N6-methyladenosine (m6A) is one of the most ubiquitous internal changes that regulate gene expression at the post-transcriptional level [19]. m6A modication regulates several phases of RNA metabolism, such as RNA translation, decay and splicing [20, 21]. The latest reported m6A demethylase FTO shows that m6A modications can be dynamically regulated [22]. However, the targets and features of m6A modication in CNS have not been explored. m6A modication can regulate neuronal function such as motor function [23], axon regeneration [24], and synapse function [25]. In addition, Hess et al reported that inhibition of FTO gene impairs neuronal activity and motor function [26]. However, the function of m6A eraser FTO on axon guiding molecules of nigro-striatal projection system in Mn-induced Parkinsonism pathogenesis has not been fully elucidated. The ndings of the current study show that FTO is implicated in regulation of motor function and mediation of axon guiding molecules against Mn-induced Parkinsonism in vitro and in vivo. These ndings show the specic mechanism of Mn-induced motor dysfunction mediated by FTO and ephrins. Page 4/32 Moreover, these ndings show that re-expression of FTO and ephrin-B2 improve motor dysfunction after Mn exposure. Materials And Methods Reagents and chemicals Manganese chloride (MnCl2·4H2O) and actinomycin D, and other chemical compounds were bought from Sigma Chemical Co. (Saint Louis, MO, USA). Cell Counting Kit-8 (CCK-8) was supplied with Transgen Institute of Biotechnology (Beijing, China). FD Rapid GolgiStain™ kit was supplied by FD NeuroTechnologies (Ellicott City, MD, USA). Enzyme-linked immunosorbent assay (ELISA) kits of mice DA was acquired from Baolai Biotechnology Institute (Jiangsu, China). Ethyl ester derivative of MA (MA2, the FTO inhibitor) was a present from Professor Caiguang Yang of the Chinese Academy of Sciences. Fluoro- Gold (FG) was purchased from Kaiji Biotechnology Co., Ltd. (Jiangsu, China). The adeno-associated virus 5 (AAV5)-FTO and AAV5-ephrin-B2 were purchased from Genecreate Biological Co., Ltd. (Wuhan, China). Lentiviral particles for over-expression of FTO (FTO-OE) were purchased from Hesheng Gene Technology Co., Ltd. (Beijing, China). Anti-m6A antibody was bought from Synaptic Systems (USA, 202003). Protein-A bead was bought from Thermo Fisher (USA, 10002D). RNasin was provided by Promega Biotechnology Co., Ltd. (Beijing, China). Rabbit antibody of FTO, methyltransferase like 3 (METTL3), α-ketoglutarate- dependent dioxygenase alkB homolog 5 (ALKBH5), YTH domain-containing family proteins 1/2 (YTHDF1/2) were bought from Proteintech Group, Inc (Wuhan, China). Rabbit antibody of tyrosine hydroxylase (TH) was bought from Cell Signaling Technology, Inc. Rabbit antibody of METTL14, ephrin- A1/3, ephrin-B1/3 were sold from ABclonal Biotechnology Co., Ltd. (Wuhan, China). Rat antibody of dopamine transporter (DAT), mouse antibody of ephrin-A5, ephrin-B2, Dopamine- and cAMP-regulated neuronal phosphoprotein 32 kDa (DARPP32) and GADPH were offered from Santa Cruz Biotechnology, Inc (Santa Cruz, CA, USA). Mouse antibody of ephrin-A2/4 was bought from Boaosen Biotechnology Co., Ltd. (Beijing, China). Horseradish peroxidase (HRP) conjugated anti-rabbit, mouse and rat secondary antibody were provided by means of Boaosen Biotechnology Co., Ltd. (Beijing, China). Real-time quantitative PCR (RT-qPCR) kit and Trizol reagent were supplied by TaKaRa Biotechnology Co, Ltd (Dalian, China). Other chemical substances were supplied through neighborhood chemical suppliers. All chemical substances reagents have been analytical grade or the pharmaceutical grade. Animals The research was carried out on adult C57BL/6 mice (20 ± 2 g; N = 350; Among them, 30 pregnant mice are needed for primary neuron culture) which have been bought from the Laboratory Animal Centre of China Medical University, Shenyang, China (SPF grade, certicate no. SCXK2013-0001). The mice were housed in plastic cages with 12-h light/dark cycle (temperature, 25 oC±1 oC, humidity, 55%±5%). Water and Food were accessible to
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