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Melatonin Induces Autophagy in Amyotrophic Lateral Sclerosis Mice via Upregulation of SIRT1

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Abstract

Amyotrophic lateral sclerosis (ALS) is the neurodegenerative disease that leads to the motor dysfunction damaged by both upper and lower motor neurons. The etiology and pathogenesis of ALS hasn’t completely been understood yet up to now, the current study suggests that autophagy plays an important role in the development of ALS. Meanwhile, melatonin is found to inhibit the progression of ALS. To this end, this study aimed to investigate the potential relation between melatonin and autophagy in ALS. The in vivo model of ALS was established to investigate the effects of melatonin in ALS. The mRNA expressions were performed to detect by RT-qPCR, and the protein levels were tested by western blot and immunofluorescence histochemistry staining. The inflammatory cytokine was applied to detect by ELISA. The results showed that melatonin dose-dependently reversed the ALS-induced survival time shortened, weight loss and rotating rod latency decrease. The expressions of both SIRT1 and Beclin-1 as well as the ratio of LC3II/LC3I were significantly upregulated in the ALS mice, while melatonin reversed the upregulation of both SIRT1 and Beclin-1 expression and LC3II/LC3I ratio in a dose-dependent manner. In contrast, melatonin dose-dependently significantly restored the ALS-induced downregulation of p62. Furthermore, SIRT1 silencing notably reduced the effect of melatonin on Beclin-1, LC3II/LC3I, and p62. Melatonin induced autophagy in the ALS mice via the upregulation of SIRT1. Thus, melatonin might act as a new agent for the treatment of ALS.

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Data Aavailability

All data generated or analyzed during this study are included in this published article.

Code Availability

Not applicable.

Abbreviations

ALS:

Amyotrophic lateral sclerosis

AMPK:

AMP-activated protein kinase

ANOVA:

Analysis of variance

Bcl-2:

B-cell lymphoma-2

Bax:

Bcl-2-Associated X

cDNA:

Complementary DNA

DAPI:

4',6-Diamidino-2-phenylindole, dihydrochloride

ELISA:

Enzyme-linked immunosorbent assay

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

IL-1β:

Interleukin-1β

IL-6:

Interleukin-6

K-M cure:

Kaplan–Meier

MN:

Motoneurons

PVDF:

Poly (vinylidene fluoride)

RIPA:

Radio-Immunoprecipitation Assay

Rpm:

Rotations per minute

RT-qPCR:

Quantitative reverse transcription PCR

SD:

Standard deviation

siRNA:

Small interferring RNA

SOD1:

Superoxide dismutase 1

TBK1:

TANK binding kinase 1

TG:

Transgenic mice expressing human SOD1G93A

TNF-α:

Tumor necrosis factor-α

WT:

Wild type mice

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Acknowledgements

We gratefully thank all technicians of Changsha Dongsheng Biotechnology Co., Ltd. (Unified social credit Code: 91430105MA4LMDL7XT), Changsha, China and Multisciences (Lianke) Biotech Co., Ltd, Hangzhou, China for performing all experiments and analyzing the rough data and providing the related technology supports. And sincerely acknowledge Prof. Dongyuan Yao at Jiangxi Provincial Neurological Institute for language editing.

Funding

This study was supported by grants from the Committee of National Natural Science Foundation of China (Grant nos. 30560042, 81160161, 81360198 and 82160255), Education Department of Jiangxi Province (Grant nos. GJJ13198 and GJJ170021), Jiangxi provincial department of science and technology (Grant nos. [2014]-47, 20142BBG70062, 20171BAB215022, and 20192BAB205043) and Health and Family Planning Commission of Jiangxi province (Grant no. 20181019).

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Author notes

  1. Xiaoping Shen, Chunyan Tang and Caihui Wei contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Jiangxi Provincial People’s Hospital, Clinical College of Nanchang Medical College, First Affiliated Hospital of Nanchang Medical College, Nanchang, 330006, Jiangxi, China

    Xiaoping Shen, Chunyan Tang, Caihui Wei, Yu Zhu & Renshi Xu

  2. Department of Neurology, Medical College of Nanchang University, Jiujiang First People’s Hospital, Affiliated Jiujiang Hospital of Nanchang University, Jiujiang, 332000, Jiangxi, China

    Xiaoping Shen

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Contributions

All authors contributed significantly to the research and preparation of the manuscript. Xiaoping Shen, Chunyan Tang, and Yu Zhu carried out cell culture and animal breed. Xiaoping Shen, Chunyan Tang, Caihui Wei, and Yu Zhu carried out western-blot and behavioral test. Xiaoping Shen, and Renshi Xu were responsible for the experimental design and writing the manuscript. Xiaoping Shen, Chunyan Tang, and Caihui Wei are the common first jointed authors. All authors read and approved the final manuscript.

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Correspondence to Renshi Xu.

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All procedures performed in studies involving human participants were in accordance with the standards upheld by the local ethics committee of Affiliated Jiujiang Hospital of Nanchang University (Approval No. 2020–9–12). The experiments were carried out strictly in line with the requirements of the International Association for the Study of Pain. All experiments were conducted in accordance with the Guide of the US National Institutes of Health (revised in 1985 [publication No. 85–23]) for the Care and Use of Laboratory Animals.

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Highlights

• Melatonin upregulates Beclin-1 and SIRT1 in ALS mice.

• Melatonin increases the survival period of ALS mice.

• Melatonin ameliorates the motor function of ALS mice.

• SIRT1 silencing reverses the therapeutic effect of melatonin on ALS.

Jiangxi Provincial People’s Hospital and Medical College of Nanchang University are the jointed finished unit and equal contribution to this study.

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Shen, X., Tang, C., Wei, C. et al. Melatonin Induces Autophagy in Amyotrophic Lateral Sclerosis Mice via Upregulation of SIRT1. Mol Neurobiol 59, 4747–4760 (2022). https://doi.org/10.1007/s12035-022-02875-7

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