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Possible Therapeutic Roles of Metallothionein-3 and Zinc in Endosome-Autophagosome-Lysosome Pathway (EALP) Dysfunction in Astrocytes

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Zinc Signaling

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Abstract

The accumulation of abnormal protein aggregates contributes to the pathological progression of diverse neurodegenerative diseases. An increasing body of evidence indicates that defects in the protein clearance system play a crucial role in this process. Cargoes delivered via endosomes, phagosomes, and autophagosomes converge on lysosomes for degradation, which process is collectively called “the endosome-autophagosome-lysosome pathway” or EALP. As such, dysfunction of lysosomes may result in the accumulation of all these upstream vesicles/cargoes and may play a key role in diverse neurodegenerative conditions.

Over the years, we found that Zn-metallothionein-3 (MT3), the brain-enriched form of metallothionein, regulates lysosomal functions in cortical astrocytes. Zn-MT3 appears to interact with β-actin and activate c-Abl kinase. As a result, Zn-MT3 plays a role in maintaining lysosomal acidity, a prerequisite for vesicle fusion as well as cargo degradation. The reported downregulation of MT3 in Alzheimer’s disease (AD), hence, may contribute to lysosomal dysfunction in AD. Of interest, raising intracellular free zinc levels also caused lysosomal acidification and normalization of degradation, even in the context of arrested autophagy. Pending further research on the mechanisms of these effects, we propose that measures increasing Zn-MT3 and/or intracellular/lysosomal free zinc may be useful in normalizing lysosomal functions in neurodegenerative conditions.

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Acknowledgments

This research was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT (NRF-2016R1E1A1A01941212 and NRF-2017M3C7A1028949 for Jae-Young Koh) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HI14C1913).

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Authors and Affiliations

  1. Neural Injury Lab, Biomedical Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea

    Ha Na Kim, Bo-Ra Seo & Jae-Young Koh

  2. Department of Bioactive Material Science, Chonbuk National University, Jeonju, South Korea

    Sook-Jeong Lee

  3. Department of Neurology, University of Ulsan College of Medicine, Seoul, South Korea

    Jae-Young Koh

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  1. Ha Na Kim
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Correspondence to Jae-Young Koh .

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  1. Molecular and Cellular Physiology Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Tokushima, Japan

    Toshiyuki Fukada

  2. Division of Integrated Life Science Graduate School of Biostudies, Kyoto University, Kyoto, Japan

    Taiho Kambe

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Kim, H.N., Seo, BR., Lee, SJ., Koh, JY. (2019). Possible Therapeutic Roles of Metallothionein-3 and Zinc in Endosome-Autophagosome-Lysosome Pathway (EALP) Dysfunction in Astrocytes. In: Fukada, T., Kambe, T. (eds) Zinc Signaling. Springer, Singapore. https://doi.org/10.1007/978-981-15-0557-7_10

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