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IRAK-M Plays A Role in the Pathology of Amyotrophic Lateral Sclerosis Through Suppressing the Activation of Microglia

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Abstract

Microglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Toll-like receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neurons in SOD1-G93A mouse model of ALS. qPCR (Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 60, 100 and 140 days of age. We established an adeno-associated virus 9 (AAV9)-based platform by which IRAK-M was targeted mostly to microglial cells to investigate whether this approach could provide a protection in the SOD1-G93A mouse. Compared with age-matched WT mice, IRAK-M mRNA level was elevated at 100 and 140 days in the anterior horn region of spinal cords in the SOD1-G93A mouse. AAV9-IRAK-M treated SOD1-G93A mice showed reduction of IL-1β mRNA levels and significant improvements in the numbers of spinal motor neurons in spinal cord. Mice also showed previously reduction of muscle atrophy. Our data revealed the dynamic changes of IRAK-M during ALS pathological progression and demonstrated that an AAV9-IRAK-M delivery was an effective and translatable therapeutic approach for ALS. These findings may help identify potential molecular targets for ALS therapy.

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Data Availability

Availability of data and materials. The datasets used and/or analyzed during the current study available from the corresponding author on reasonable request.

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Acknowledgements

We thank Dr. Wang Honghao for kind suggestions to our manuscript and experimental techniques.

Funding

This work was supported by the National Natural Science Foundation of China [grant numbers 81901239, 82171354]; and the Science and Technology Projects in Guangzhou [grant number 202201010924].

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Author notes

  1. Xinghua Zhong and Chuqiao Li contributed equally to this work and share first authorship.

Authors and Affiliations

  1. Department of Neurology, Nanfang Hospital, Southern Medical University, No. 1838, North Guangzhou Avenue, Guangzhou, 510515, Guangdong, China

    Xinghua Zhong, Chuqiao Li, Yanran Li, Yingyi Huang, Jingsi Liu, Anqi Jiang, Jinyu Chen & Yu Peng

  2. Department of Neurology, Guangzhou First People’s Hospital, School of Medicine, Southern China University of Technology, Guangzhou, China

    Yu Peng

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  1. Xinghua Zhong
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Contributions

ZX performed most of the experiments. LC mainly performed confocal imaging analysis and pathologic analysis. HY genotyped the animals. LJ and JA performed some preliminary experiments. ZX and LY performed data analysis. ZX and CJ wrote the manuscript. PY conceived the study. All authors contributed to the finalization and approved the content of the manuscript.

Corresponding authors

Correspondence to Jinyu Chen or Yu Peng.

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Ethics Approval

All animal experiments were conducted according to the Regulations for the Administration of Affairs Concerning Experimental Animals (China) and were approved by the Southern Medical University Animal Ethics Committee.

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This study did not involve human subjects.

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This study did not involve patients.

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The authors have no relevant financial or non-financial interests to disclose.

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Zhong, X., Li, C., Li, Y. et al. IRAK-M Plays A Role in the Pathology of Amyotrophic Lateral Sclerosis Through Suppressing the Activation of Microglia. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04065-z

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