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Anti-apoptotic Splicing Variant of AIMP2 Recover Mutant SOD1-Induced Neuronal Cell Death

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Abstract

Although a couple of studies have reported that mutant superoxide dismutase 1 (SOD1), one of the causative genes of familial amyotrophic lateral, interacts physically with lysyl-tRNA synthetase (KARS1) by a gain of function, there is limited evidence regarding the detailed mechanism about how the interaction leads to neuronal cell death. Our results indicated that the aminoacyl-tRNA synthetase-interacting multi-functional protein 2 (AIMP2) mediated cell death upon the interplay between mutant SOD1 and KARS1 in ALS. Binding of mutant SOD1 with KARS1 led to the release of AIMP2 from its original binding partner KARS1, and the free form of AIMP2 induced TRAF2 degradation followed by TNF-α-induced cell death. We also suggest a therapeutic application that overexpression of DX2, the exon 2-deleted antagonistic splicing variant of AIMP2 (AIMP2-DX2), reduced neuronal cell death in the ALS mouse model. Expression of DX2 suppressed TRAF2 degradation and TNF-α-induced cell death by competing mode of action against full-length AIMP2. Motor neuron differentiated form iPSC showed a resistance in neuronal cell death after DX2 administration. Further, intrathecal administration of DX2-coding adeno-associated virus (AAV) improved locomotive activity and survival in a mutant SOD1-induced ALS mouse model. Taken together, these results indicated that DX2 could prolong life span and delay the ALS symptoms through compensation in neuronal inflammation.

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Data Availability

Most of datasets generated or analyzed during the current study are included in this published article and available from the corresponding author on reasonable request.

Abbreviations

AAV:

Adeno-associated virus

AIMP2:

Aminoacyl-tRNA synthetase-interacting multi-functional protein 2

ALS:

Amyotrophic lateral sclerosis

DX2:

Exon 2-deleted splicing variant of AIMP2

KARS1:

Lysyl-tRNA synthetase

MSC:

multi-tRNA synthetase complex

SOD1:

superoxide dismutase 1

TNF-α:

tumor necrosis factor-α

TRAF2:

TNF receptor-associated factor 2

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Funding

This work was supported by the Basic Science Research Program, Ministry of Science and ICT (NRF-2017R1A5A2014768, 2018R1A2B3008483, 2019R1A2C1006752, 2021R1A3B1076605, and NRF-2022R1A2C2009281); a grant from the Global Frontier Project (NRF-2016M3A6A4929906) of the National Research Foundation, Ministry of Science and ICT of Korea; and partially the Yonsei University Research Fund of 2020–22-0358, 2020–22-0356, and 2021–22-0061. And the research was supported by a grant (21153MFDS601) from Ministry of Food and Drug Safety in 2022.

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  1. Myung Geun Kook and Mi Ran Byun contributed equally to this work.

Authors and Affiliations

  1. College of Veterinary Medicine and Research Institute for Veterinary Science, Seoul National University, Seoul, 08826, Republic of Korea

    Myung Geun Kook & Kyung-Sun Kang

  2. Adult Stem Cell Research Center, College of Veterinary Medicine, Seoul National University, Seoul, 08826, Republic of Korea

    Myung Geun Kook & Kyung-Sun Kang

  3. Department of Pharmacology, College of Pharmacy, Kyung Hee University, Seoul, 02447, Republic of Korea

    Mi Ran Byun, Soo Min Lee, Min Hak Lee, Dae Hoon Lee, Eui-Jin Lee & Jin Woo Choi

  4. Department of Biomedicinal and Pharmaceutical Sciences, Kyung Hee University, Seoul, 02447, Republic of Korea

    Mi Ran Byun & Kyunghwa Baek

  5. Department of Pharmacology, College of Dentistry and Research Institute of Oral Science, Gangneung-Wonju National University, Gangwon-do, 25457, Republic of Korea

    Soo Min Lee, Min Hak Lee, Dae Hoon Lee, Hyung Been Lee, Eui-Jin Lee & Jin Woo Choi

  6. Generoath Ltd, Seoul, 04168, Republic of Korea

    Kyunghwa Baek

  7. Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy and College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon, 21983, Republic of Korea

    Sunghoon Kim

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Contributions

M. G. K., M. R. B., S. M. L., and J. W. C. analyzed the results and wrote the manuscript. M. R. B., M. G. K., S. M. L., H. B. L., M. H. L., and D. H. L. performed the experiments. S. H. K. and K. S. K. contributed to the interpretation and discussion of the results. K. H. B. and J. W. C. leaded the research project.

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Correspondence to Kyung-Sun Kang or Jin Woo Choi.

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All experimental procedures were performed in accordance with guidelines of the Seoul National University Institutional Animal Care and Use Committee (SNUIACUC, August 7, 2017). Our local ethics committee “SNUIACUC” approved the present study (Approval No. SNU-170807–1).

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Kook, M.G., Byun, M.R., Lee, S.M. et al. Anti-apoptotic Splicing Variant of AIMP2 Recover Mutant SOD1-Induced Neuronal Cell Death. Mol Neurobiol 60, 145–159 (2023). https://doi.org/10.1007/s12035-022-03073-1

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