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Yorkie Regulates Neurodegeneration Through Canonical Pathway and Innate Immune Response

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Abstract

Expansion of CAG repeats in certain genes has long been known to be associated with neurodegenerastion, but the quest to identity the underlying mechanisms is still on. Here, we analyzed the role of Yorkie, the coactivator of the Hippo pathway, and provide evidence to state that it is a robust genetic modifier of polyglutamine (PolyQ)-mediated neurodegeneration. Yorkie reduces the pathogenicity of inclusion bodies in the cell by activating cyclin E and bantam, rather than by preventing apoptosis through DIAP1. PolyQ aggregates inhibit Yorkie functioning at the protein, rather than the transcript level, and this is probably accomplished by the interaction between PolyQ and Yorkie. We show that PolyQ aggregates upregulate expression of antimicrobial peptides (AMPs) and Yorkie negatively regulates immune deficiency (IMD) and Toll pathways through relish and cactus, respectively, thus reducing AMPs and mitigating PolyQ affects. These studies strongly suggest a novel mechanism of suppression of PolyQ-mediated neurotoxicity by Yorkie through multiple channels.

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Acknowledgements

We thank Dr. Duojia Pan (HHMI-John Hopkins School of Medicine) and Dr. Kenneth Irvine (HHMI-Ruetger State University, USA) for anti-Yorkie antibody. We thank Parsa Kazemi-Esfarjani and Bloomington Stock Centre for transgenic flies. This work was supported by research grant from Department of Science and Technology and Department of Biotechnology Government of India, New Delhi. We thank Department of Science and Technology, India, for providing National Facility for confocal microscope.

Authors’ Contribution

Conceived and designed the experiments: SKD and MGT. Performed the experiments: SKD. Analyzed the data: SKD and MGT. Wrote the paper: SKD and MGT. All authors reviewed the manuscript.

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  1. Cytogenetics Laboratory, Department of Zoology, Banaras Hindu University, Varanasi, 221005, India

    Sandeep Kumar Dubey & Madhu G. Tapadia

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Correspondence to Madhu G. Tapadia.

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This work was supported by Department of Science and Technology (DST) and Department of Biotechnology (DBT), Government of India, New Delhi, India.

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The authors declare that they have no conflict of interest.

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Dubey, S.K., Tapadia, M.G. Yorkie Regulates Neurodegeneration Through Canonical Pathway and Innate Immune Response. Mol Neurobiol 55, 1193–1207 (2018). https://doi.org/10.1007/s12035-017-0388-7

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