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Inhibition of Transglutaminase Exacerbates Polyglutamine-Induced Neurotoxicity by Increasing the Aggregation of Mutant Ataxin-3 in an SCA3 Drosophila Model

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Abstract

Transglutaminases (TGs) comprise a family of Ca2+-dependent enzymes that catalyze protein cross-linking, which include nine family members in humans but only a single homolog in Drosophila with three conserved domains. Drosophila Tg plays important roles in cuticle morphogenesis, hemolymph clotting, and innate immunity. Mammalian tissue TG (TG2) is involved in polyglutamine diseases (polyQ diseases), and TG6 has been identified as a causative gene of a novel spinocerebellar ataxia, SCA35. Using a well-established SCA3 fly model, we found that RNA interference-mediated suppression of Tg aggravated polyQ-induced neurodegenerative phenotypes. The administration of cystamine, a known effective Tg inhibitor, enhanced ommatidial degeneration in SCA3 flies. We also demonstrated that the aggregates of pathogenic ataxin-3 increased greatly, when the Tg activity was repressed. These findings indicate that Tg is crucial for polyQ-induced neurotoxicity because Tg ablation resulted in more severe neurodegeneration due to the elevated accumulation of insoluble ataxin-3 complexes in the SCA3 Drosophila model.

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Acknowledgments

We would like to thank Dr. Beisha Tang for providing pertinent advice, sharing detailed information of SCA35 patients, and giving great inspiration, and Dr. Nancy M. Bonini for providing fly lines that express full-length versions of ataxin-3. We would also thank the Bloomington Drosophila Stock Center and the Vienna Drosophila RNAi Center for fly stocks. We thank Core Facility of Drosophila Resource and Technique, SIBCB, CAS for assistance with microinjection and Electron Microscope Room at the Hunan Normal University for assistance with SEM imaging. This work was supported in part by National Natural Science Foundation of China (Grant Number: 81071028, 81172513), Program for New Century Excellent Talents in University (Grant Number: NCET-10-0832), National Key Basic Research Program (973 program) (Grant Number: 2012CB944600), Hunan Provincial Innovation Foundation for Postgraduate (Grant Number: CX2013B091), and Scholarship for Excellent Doctoral Student in Central South University.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. The State Key Laboratory of Medical Genetics & School of Life Sciences, Central South University, Changsha, 410078, Hunan, China

    Yunting Lin, Hua He, Ting Zhu & Ranhui Duan

  2. The Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China

    Yingying Luo

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  1. Yunting Lin
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Correspondence to Ranhui Duan.

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Lin, Y., He, H., Luo, Y. et al. Inhibition of Transglutaminase Exacerbates Polyglutamine-Induced Neurotoxicity by Increasing the Aggregation of Mutant Ataxin-3 in an SCA3 Drosophila Model. Neurotox Res 27, 259–267 (2015). https://doi.org/10.1007/s12640-014-9506-8

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  • DOI: https://doi.org/10.1007/s12640-014-9506-8

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