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

Myung Geun Kook, Mi Ran Byun, Soo Min Lee, Min Hak Lee, Dae Hoon Lee, Hyung Been Lee, Eui Jin Lee, Kyunghwa Baek, Sunghoon Kim, Kyung Sun Kang, Jin Woo Choi

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


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.

Original languageEnglish
Pages (from-to)145-159
Number of pages15
JournalMolecular Neurobiology
Issue number1
Publication statusPublished - 2023 Jan

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

All Science Journal Classification (ASJC) codes

  • Neurology
  • Cellular and Molecular Neuroscience
  • Neuroscience (miscellaneous)


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