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Knockdown of Golgi Stress-Responsive Caspase-2 Ameliorates HLD17-Associated AIMP2 Mutant-Mediated Inhibition of Oligodendroglial Cell Morphological Differentiation

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Abstract

Hypomyelinating leukodystrophy 17 is an autosomal recessive disease affecting myelin-forming oligodendroglial cells in the central nervous system. The gene responsible for HLD17 encodes aminoacyl-tRNA synthase complex-interacting multifunctional protein 2, whose product proteins form a scaffold that supports aminoacyl-tRNA synthetases throughout the cell body. Here we show that the HLD17-associated nonsense mutation (Tyr35-to-Ter [Y35X]) of AIMP2 localizes AIMP2 proteins as aggregates into the Golgi bodies in mouse oligodendroglial FBD-102b cells. Wild type AIMP2 proteins, in contrast, are distributed throughout the cell body. Expression of the Y35X mutant proteins, but not the wild type proteins, in cells upregulates Golgi stress signaling involving caspase-2 activation. Cells expressing the wild type proteins exhibit differentiated phenotypes with web-like structures bearing many processes following the induction of differentiation, whereas cells expressing the Y35X mutant proteins fail to differentiate. Furthermore, CASP2 knockdown but not control knockdown reverses the phenotypes of cells expressing the mutant proteins. These results suggest that HLD17-associated AIMP2 mutant proteins are localized in the Golgi bodies where their proteins stimulate Golgi stress-responsive CASP2 to inhibit differentiation; this effect is ameliorated by knockdown of CASP2. These findings may reveal some of the molecular and cellular pathological mechanisms underlying HLD17 and possible approaches to ameliorating the disease’s effects.

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Acknowledgements

We thank Dr. Yoshihiro Hayashi (Tokyo University of Pharmacy and Life Sciences) for his insightful comments they provided throughout this study. We also thank Dr. Chris Rowthorn (Chris Rowthorn Japan, Co. Ltd.) for English proofreading.

Funding

This work was supported by Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science, and Technology (MEXT). This work was also supported by Grants-in-Aid for Medical Scientific Research from the Japanese Ministry of Health, Labor, and Welfare (MHLW).

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Authors and Affiliations

  1. Laboratory of Molecular Neurology, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Arisa Ochiai, Sui Sawaguchi, Shiori Memezawa, Yoichi Seki, Takako Morimoto & Junji Yamauchi

  2. Tsumura Research Laboratories, Tsumura & Co., Inashiki, Ibaraki, 200-1192, Japan

    Hiroaki Oizumi, Katsuya Ohbuchi, Masahiro Yamamoto & Kazushige Mizoguchi

  3. Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo, 157-8535, Japan

    Yuki Miyamoto & Junji Yamauchi

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  1. Arisa Ochiai
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Contributions

JY designed and organized this study. YM and JY wrote and edited this manuscript. AO, SS, YS, and TM performed the experiments. AO and SS performed the statistical analyses. KO, MY, and KM provided unpublished materials.

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Correspondence to Junji Yamauchi.

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Ochiai, A., Sawaguchi, S., Memezawa, S. et al. Knockdown of Golgi Stress-Responsive Caspase-2 Ameliorates HLD17-Associated AIMP2 Mutant-Mediated Inhibition of Oligodendroglial Cell Morphological Differentiation. Neurochem Res 47, 2617–2631 (2022). https://doi.org/10.1007/s11064-021-03451-6

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  • DOI: https://doi.org/10.1007/s11064-021-03451-6

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