FTO-targeted siRNA delivery by MSC-derived exosomes synergistically alleviates dopaminergic neuronal death in Parkinson&apos;s disease via m6A-dependent regulation of ATM mRNA

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Abstract

Background

Parkinson's disease (PD), characterized by the progressive loss of dopaminergic neurons in the substantia nigra and striatum of brain, seriously threatens human health, and is still lack of effective treatment. Dysregulation of N6-methyladenosine (m6A) modification has been implicated in PD pathogenesis. However, how m6A modification regulates dopaminergic neuronal death in PD remains elusive. Mesenchymal stem cell-derived exosomes (MSC-Exo) have been shown to be effective for treating central nervous disorders. We thus propose that the m6A demethylase FTO-targeted siRNAs (si-FTO) may be encapsulated in MSC-Exo (Exo-siFTO) as a synergistic therapy against dopaminergic neuronal death in PD.

Methods

In this study, the effect of m6A demethylase FTO on dopaminergic neuronal death was evaluated both in vivo and in vitro using a MPTP-treated mice model and a MPP + -induced MN9D cellular model, respectively. The mechanism through which FTO influences dopaminergic neuronal death in PD was investigated with qRT-PCR, western blot, immumohistochemical staining, immunofluorescent staining and flow cytometry. The therapeutic roles of MSC-Exo containing si-FTO were examined in PD models in vivo and in vitro.

Results

The total m6A level was significantly decreased and FTO expression was increased in PD models in vivo and in vitro. FTO was found to promote the expression of cellular death-related factor ataxia telangiectasia mutated (ATM) via m6A-dependent stabilization of ATM mRNA in dopaminergic neurons. Knockdown of FTO by si-FTO concomitantly suppressed upregulation of α-Synuclein (α-Syn) and downregulation of tyrosine hydroxylase (TH), and alleviated neuronal death in PD models. Moreover, MSC-Exo were utilized to successfully deliver si-FTO to the striatum of animal brain, resulting in the significant suppression of α-Syn expression and dopaminergic neuronal death, and recovery of TH expression in the brain of PD mice.

Conclusions

MSC-Exo delivery of si-FTO synergistically alleviates dopaminergic neuronal death in PD via m6A-dependent regulation of ATM mRNA.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-023-04461-4.

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limma powers differential expression analyses for RNA-sequencing and microarray studies

Matthew E. Ritchie, Belinda Phipson, Di Wu … (2015)

limma is an R/Bioconductor software package that provides an integrated solution for analysing data from gene expression experiments. It contains rich features for handling complex experimental designs and for information borrowing to overcome the problem of small sample sizes. Over the past decade, limma has been a popular choice for gene discovery through differential expression analyses of microarray and high-throughput PCR data. The package contains particularly strong facilities for reading, normalizing and exploring such data. Recently, the capabilities of limma have been significantly expanded in two important directions. First, the package can now perform both differential expression and differential splicing analyses of RNA sequencing (RNA-seq) data. All the downstream analysis tools previously restricted to microarray data are now available for RNA-seq as well. These capabilities allow users to analyse both RNA-seq and microarray data with very similar pipelines. Second, the package is now able to go past the traditional gene-wise expression analyses in a variety of ways, analysing expression profiles in terms of co-regulated sets of genes or in terms of higher-order expression signatures. This provides enhanced possibilities for biological interpretation of gene expression differences. This article reviews the philosophy and design of the limma package, summarizing both new and historical features, with an emphasis on recent enhancements and features that have not been previously described.

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ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.

S Matsuoka, B. Ballif, A Smogorzewska … (2007)

Cellular responses to DNA damage are mediated by a number of protein kinases, including ATM (ataxia telangiectasia mutated) and ATR (ATM and Rad3-related). The outlines of the signal transduction portion of this pathway are known, but little is known about the physiological scope of the DNA damage response (DDR). We performed a large-scale proteomic analysis of proteins phosphorylated in response to DNA damage on consensus sites recognized by ATM and ATR and identified more than 900 regulated phosphorylation sites encompassing over 700 proteins. Functional analysis of a subset of this data set indicated that this list is highly enriched for proteins involved in the DDR. This set of proteins is highly interconnected, and we identified a large number of protein modules and networks not previously linked to the DDR. This database paints a much broader landscape for the DDR than was previously appreciated and opens new avenues of investigation into the responses to DNA damage in mammals.

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Activation and regulation of ATM kinase activity in response to DNA double-strand breaks.

Norman Lee, Tanya T. Paull (2007)

The ataxia-telangiectasia-mutated (ATM) protein kinase is rapidly and specifically activated in response to DNA double-strand breaks in eukaryotic cells. In this review, we summarize recent insights into the mechanism of ATM activation, focusing on the role of the Mre11/Rad50/Nbs1 (MRN) complex in this process. We also compare observations of the ATM activation process in different biological systems and highlight potential candidates for cellular factors that may participate in regulating ATM activity in human cells.

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Author and article information

Contributors

Yuanyuan Zhang: gzzjzyy8034@163.com

Xiao Cheng: chengxiaolucky@126.com

Zhengqiang Yuan: yuanzq@gdut.edu.cn

Jie Zan: zanj@gdut.edu.cn

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 22 September 2023

Publication date PMC-release: 22 September 2023

Publication date Collection: 2023

Volume: 21

Electronic Location Identifier: 652

Affiliations

[1 ]School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, ( https://ror.org/04azbjn80) Guangzhou, 510006 China

[2 ]GRID grid.459864.2, ISNI 0000 0004 6005 705X, Department of Radiology, , Guangzhou Panyu Central Hospital, ; Guangzhou, 511400 China

[3 ]GRID grid.410737.6, ISNI 0000 0000 8653 1072, The affiliated TCM Hospital of Guangzhou Medical University, ; Guangzhou, 510130 China

[4 ]State Key Laboratory of Dampness, Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, ( https://ror.org/03qb7bg95) Guangzhou, Guangdong China

[5 ]Provincial Key Laboratory of Research on Emergency in TCM, Guangzhou, China

[6 ]Department of Neurology, Guangdong Provincial Hospital of Traditional Chinese Medicine, ( https://ror.org/01gb3y148) Guangzhou, 510120 China

Article

Publisher ID: 4461

DOI: 10.1186/s12967-023-04461-4

PMC ID: 10515429

PubMed ID: 37737187

SO-VID: 09a417a4-7281-48c3-84b3-c8ddffc51e4f

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 24 May 2023

Date accepted : 21 August 2023

Funding

Funded by: Guangzhou Basic and Applied Basic Research Foundation

Award ID: 2023A03J0744

Award Recipient : Yan Geng

Custom metadata

ScienceOpen disciplines: Medicine

Keywords: parkinson’s disease,n6-methyladenosine modification,fto,sirna,exosomes

Data availability:

ScienceOpen disciplines: Medicine

Keywords: parkinson’s disease, n6-methyladenosine modification, fto, sirna, exosomes

FTO-targeted siRNA delivery by MSC-derived exosomes synergistically alleviates dopaminergic neuronal death in Parkinson's disease via m6A-dependent regulation of ATM mRNA

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Abstract

Background

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Supplementary Information

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RNA drug delivery

Most cited references 58

limma powers differential expression analyses for RNA-sequencing and microarray studies

ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage.

Activation and regulation of ATM kinase activity in response to DNA double-strand breaks.

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