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Molecular Association of Glia Maturation Factor with the Autophagic Machinery in Rat Dopaminergic Neurons: a Role for Endoplasmic Reticulum Stress and MAPK Activation

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Abstract

Parkinson’s disease (PD) is one of the several neurodegenerative diseases where accumulation of aggregated proteins like α-synuclein occurs. Dysfunction in autophagy leading to this protein build-up and subsequent dopaminergic neurodegeneration may be one of the causes of PD. The mechanisms that impair autophagy remain poorly understood. 1-Methyl-4-phenylpiridium ion (MPP+) is a neurotoxin that induces experimental PD in vitro. Our studies have shown that glia maturation factor (GMF), a brain-localized inflammatory protein, induces dopaminergic neurodegeneration in PD and that suppression of GMF prevents MPP+-induced loss of dopaminergic neurons. In the present study, we demonstrate a molecular action of GMF on the autophagic machinery resulting in dopaminergic neuronal loss and propose GMF-mediated autophagic dysfunction as one of the contributing factors in PD progression. Using dopaminergic N27 neurons, primary neurons from wild type (WT), and GMF-deficient (GMF-KO) mice, we show that GMF and MPP+ enhanced expression of MAPKs increased the mammalian target of rapamycin (mTOR) activation and endoplasmic reticulum stress markers such as phospho-eukaryotic translation initiation factor 2 alpha kinase 3 (p-PERK) and inositol-requiring enzyme 1α (IRE1α). Further, GMF and MPP+ reduced Beclin 1, focal adhesion kinase (FAK) family-interacting protein of 200 kD (FIP200), and autophagy-related proteins (ATGs) 3, 5, 7, 16L, and 12. The combined results demonstrate that GMF affects autophagy through autophagosome formation with significantly reduced lysosomal-associated membrane protein 1/2, and the number of autophagic acidic vesicles. Using primary neurons, we show that MPP+ treatment leads to differential expression and localization of p62/sequestosome and in GMF-KO neurons, there was a marked increase in p62 staining implying autophagy deficiency with very little co-localization of α-synuclein and p62 as compared with WT neurons. Collectively, this study provides a bidirectional role for GMF in executing dopaminergic neuronal death mediated by autophagy that is relevant to PD.

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Acknowledgements

This work was supported by Veterans Affairs Merit Award I01BX002477 and National Institutes of Health Grants AG048205 and NS073670 to AZ. We would like to thank Dr. Alexander Jurkevich, Associate Director of Molecular Cytology core, University of Missouri, Columbia-MO for his help in preparation and validation of confocal images.

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  1. Harry S. Truman Memorial Veterans Hospital, Columbia, MO, USA

    Govindhasamy Pushpavathi Selvakumar, Shankar S Iyer, Duraisamy Kempuraj, Mohammad Ejaz Ahmed, Ramasamy Thangavel, Iuliia Dubova, Sudhanshu P. Raikwar, Smita Zaheer & Asgar Zaheer

  2. Department of Neurology, and Center for Translational Neuroscience, School of Medicine-University of Missouri, M741A Medical Science Building, 1 Hospital Drive, Columbia, MO, USA

    Govindhasamy Pushpavathi Selvakumar, Shankar S Iyer, Duraisamy Kempuraj, Mohammad Ejaz Ahmed, Ramasamy Thangavel, Sudhanshu P. Raikwar & Asgar Zaheer

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  1. Govindhasamy Pushpavathi Selvakumar
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Correspondence to Asgar Zaheer.

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Selvakumar, G.P., Iyer, S.S., Kempuraj, D. et al. Molecular Association of Glia Maturation Factor with the Autophagic Machinery in Rat Dopaminergic Neurons: a Role for Endoplasmic Reticulum Stress and MAPK Activation. Mol Neurobiol 56, 3865–3881 (2019). https://doi.org/10.1007/s12035-018-1340-1

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