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Lanosterol Suppresses the Aggregation and Cytotoxicity of Misfolded Proteins Linked with Neurodegenerative Diseases

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Abstract

Accumulation of misfolded or aberrant proteins in neuronal cells is linked with neurodegeneration and other pathologies. Which molecular mechanisms fail and cause inappropriate folding of proteins and what is their relationship to cellular toxicity is not well known. How does it happen and what are the probable therapeutic or molecular approaches to counter them are also not clear. Here, we demonstrate that treatment of lanosterol diminishes aberrant proteotoxic aggregation and mitigates their cytotoxicity via induced expression of co-chaperone CHIP and elevated autophagy. The addition of lanosterol not only reduces aggregation of mutant bonafide misfolded proteins but also effectively prevents accumulation of various mutant disease-prone proteotoxic proteins. Finally, we observed that lanosterol mitigates cytotoxicity in cells, mediated by different stress-inducing agents. Taken together, our present results suggest that upregulation of cellular molecular chaperones, primarily using small molecules, can probably offer an efficient therapeutic approach in the future against misfolding of different disease-causing proteins and neurodegenerative disorders.

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Acknowledgements

This work was supported by the Department of Biotechnology, Government of India. AM was supported by Ramalinganswami Fellowship (BT/RLF/Reentry/11/2010) and Extra Mural Research Funding (Individual Centric): Science and Engineering Research Board (SERB) EMR/2016/000716, Department of Science and Technology, Government of India. AU was supported by a research fellowship from University Grants Commission, Council of Scientific and Industrial Research, Government of India. The authors would like to thank Mr. Bharat Pareek for his technical assistance and entire lab management during the manuscript preparation. We also thank to all for gifted plasmids: Dr. Csaba soti (Department of Medical Chemistry, Semmelweis University, Budapest, Hungary) for GFP-wtCAT and GFP-Δ9CAT constructs, Dr. Hilal Lashuel (Laboratory of Molecular and Chemical Biology of Neurodegeneration, Brain Mind Institute, School of Life Sciences, for α-Synuclein and α-Synuclein-S87A plasmids, Ecole Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland), Dr. A Tunnacliffe (Department of Chemical Engineering and Biotechnology, University of Cambridge, Cambridge, UK) for EGFP-HDQ23 and EGFP-HDQ74 constructs, Dr. Elizabeth Fisher (UCL Institute of Neurology, Queen Square, London) for pF141 pAcGFP1 SOD1WT and pF148 pSOD1G37RAcGFP1 plasmids, Dr. Henry L. Paulson (The University of Michigan Health System, Department of Neurology, Ann Arbor, MI) for pEGFP-C1-Ataxin3Q28 and pEGFP-C1-Ataxin3Q84 constructs, and Dr. William Kaelin from Dana Farber Cancer Institute and the Howard Hughes Medical Institute for luciferase-pcDNA3 plasmid.

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  1. Cellular and Molecular Neurobiology Unit, Indian Institute of Technology Jodhpur, Jodhpur, Rajasthan, 342011, India

    Arun Upadhyay, Ayeman Amanullah, Ribhav Mishra & Amit Mishra

  2. Centre for Biosciences and Biomedical Engineering, Indian Institute of Technology Indore, Indore, Madhya Pradesh, 453552, India

    Amit Kumar

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  1. Arun Upadhyay
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Correspondence to Amit Mishra.

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Arun Upadhyay and Ayeman Amanullah contributed equally to this work.

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Upadhyay, A., Amanullah, A., Mishra, R. et al. Lanosterol Suppresses the Aggregation and Cytotoxicity of Misfolded Proteins Linked with Neurodegenerative Diseases. Mol Neurobiol 55, 1169–1182 (2018). https://doi.org/10.1007/s12035-016-0377-2

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