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An Increase in Peroxiredoxin 6 Expression Induces Neurotoxic A1 Astrocytes in the Lumbar Spinal Cord of Amyotrophic Lateral Sclerosis Mice Model

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Abstract

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with selective degeneration of motor neurons. It has been reported that an increase in the levels of inflammatory cytokines and glial cells such as reactive astrocytes is closely involved in the pathological progression of ALS. Recently, the levels of neuropathic cytotoxic (A1) astrocytes among reactive astrocytes have reportedly increased in the central nervous system of ALS mice, which induce motor neuron degeneration through the production of inflammatory cytokines and secretion of neuropathic factors. Hence, elucidating the induction mechanism of A1 astrocytes in ALS is important to understand the mechanism of disease progression in ALS. In this study, we observed that the expression of peroxiredoxin 6 (PRDX6), a member of the peroxiredoxin family, was markedly upregulated in astrocytes of the lumbar spinal cord of SOD1G93A mice model for ALS. Additionally, when PRDX6 was transiently transfected into the mouse astrocyte cell line C8-D1A and human astrocytoma cell line U-251 MG, the mRNA expression of complement C3 (a marker for A1 astrocyte phenotype) and inflammatory cytokines was increased. Furthermore, the mRNA expression of C3 and inflammatory cytokine was increased in C8-D1A and U-251 MG cells stably expressing PRDX6, and the increased mRNA expression was significantly suppressed by MJ33 (lithium[1-hexadecoxy-3-(2,2,2-trifluoroethoxy) propan-2-yl] methyl phosphate), an inhibitor of the phospholipase A2 activity of PRDX6. Our results suggest that the expression of PRDX6 in astrocytes plays an important role in the induction of A1 astrocytes and expression of inflammatory cytokines in the ALS mice model.

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

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Acknowledgements

We would like to thank Editage (www.editage.com) for English language editing. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Laboratory of Pharmacotherapeutics, Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka, 573-0101, Japan

    Akiko Yamamuro-Tanabe, Yurika Mukai, Wataru Kojima, Siyuan Zheng, Naoko Matsumoto, Shoho Takada, Mao Mizuhara, Yuki Ishimaru & Yasuhiro Yoshioka

  2. Laboratory of Pharmacology, School of Pharmacy, Nihon University, Chiba, 274-8555, Japan

    Yasuhiro Kosuge

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Contributions

AY-T designed the study, performed most of the experiments, and wrote the original draft. YM, WK, SZ, NM, ST, MM, YK, and YI performed some experiments. YY designed the study and reviewed and edited the manuscript.

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Correspondence to Yasuhiro Yoshioka.

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Approval was granted by the Safety Committee for Recombinant DNA Experiments of Setsunan University (Approval ID: K08-13/08.04.14.2.S.017) and Animal Care and Use Committee of Nihon University (Approval Nos: AP13P001 and AP19PHA026).

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Yamamuro-Tanabe, A., Mukai, Y., Kojima, W. et al. An Increase in Peroxiredoxin 6 Expression Induces Neurotoxic A1 Astrocytes in the Lumbar Spinal Cord of Amyotrophic Lateral Sclerosis Mice Model. Neurochem Res 48, 3571–3584 (2023). https://doi.org/10.1007/s11064-023-04003-w

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