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Spermine protects alpha-synuclein expressing dopaminergic neurons from manganese-induced degeneration

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Abstract

Manganese exposure is among the many environmental risk factors linked to the progression of neurodegenerative diseases, such as manganese-induced parkinsonism. In animal models, chronic exposure to manganese causes loss of cell viability, neurodegeneration, and functional deficits. Polyamines, such as spermine, have been shown to rescue animals from age-induced neurodegeneration in an autophagy-dependent manner; nonetheless, it is not understood whether polyamines can prevent manganese-induced toxicity. In this study, we used two model systems, the Caenorhabditis elegans UA44 strain and SK-MEL-28 cells, both expressing the protein alpha-synuclein (α-syn) to determine whether spermine could ameliorate manganese-induced toxicity. Manganese caused a substantial reduction in the viability of SK-MEL-28 cells and hastened neurodegeneration in the UA44 strain. Spermine protected both the SK-MEL-28 cells and the UA44 strain from manganese-induced toxicity. Spermine also reduced the age-associated neurodegeneration observed in the UA44 strain compared with a control strain without α-syn expression and led to improved avoidance behavior in a functional assay. Treatment with berenil, an inhibitor of polyamine catabolism, which leads to increased intracellular polyamine levels, also showed similar cellular protection against manganese toxicity. While both translation blocker cycloheximide and autophagy blocker chloroquine caused a reduction in the cytoprotective effect of spermine, transcription blocker actinomycin D had no effect. This study provides new insights on the effect of spermine in preventing manganese-induced toxicity, which is most likely via translational regulation of several candidate genes, including those of autophagy. Thus, our results indicate that polyamines positively influence neuronal health, even when exposed to high levels of manganese and α-syn, and supplementing polyamines through diet might delay the onset of diseases involving degeneration of dopaminergic neurons.

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Acknowledgments

We thank Dr. Santhoshkumar T R of Rajiv Gandhi Centre for Biotechnology, Trivandrum, for providing us the SK-MEL-28 cell line. We are grateful to Aswathy A Rejani and Rasitha S Kanakalatha for technical help with the C. elegans experiments.

Funding

This work was supported by SCTIMST, Thiruvananthapuram, Kerala, India.

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  1. Comprehensive Care Centre for Movement Disorders, Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

    Bejoy Vijayan, Swapna Nandakumar & Asha Kishore

  2. Division of Molecular Medicine, Department of Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India

    Vishnu Raj & Anoopkumar Thekkuveettil

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  1. Bejoy Vijayan
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Asha Kishore and Anoopkumar Thekkuveettil both authors shared equal responsibilities

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Fig. S1

Pattern of expression and localization of α-syn in SK-MEL-28 cells (representative images). Scale bar is 100 μM. α-syn, α-synuclein. (PNG 218 kb)

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Vijayan, B., Raj, V., Nandakumar, S. et al. Spermine protects alpha-synuclein expressing dopaminergic neurons from manganese-induced degeneration. Cell Biol Toxicol 35, 147–159 (2019). https://doi.org/10.1007/s10565-018-09449-1

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