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Withaferin A Induces Heat Shock Response and Ameliorates Disease Progression in a Mouse Model of Huntington’s Disease

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Abstract

Impairment of proteostasis network is one of the characteristic features of many age-related neurodegenerative disorders including autosomal dominantly inherited Huntington’s disease (HD). In HD, N-terminal portion of mutant huntingtin protein containing expanded polyglutamine repeats accumulates as inclusion bodies and leads to progressive deterioration of various cellular functioning including proteostasis network. Here we report that Withaferin A (a small bioactive molecule derived from Indian medicinal plant, Withania somnifera) partially rescues defective proteostasis by activating heat shock response (HSR) and delays the disease progression in a HD mouse model. Exposure of Withaferin A activates HSF1 and induces the expression of HSP70 chaperones in an in vitro cell culture system and also suppresses mutant huntingtin aggregation in a cellular model of HD. Withaferin A treatment to HD mice considerably increased their lifespan as well as restored progressive motor behavioral deficits and declined body weight. Biochemical studies confirmed the activation of HSR and global decrease in mutant huntingtin aggregates load accompanied with improvement of striatal function in Withaferin A-treated HD mouse brain. Withaferin A-treated HD mice also exhibit significant decrease in inflammatory processes as evident from the decreased microglial activation. These results indicate immense potential of Withaferin A for the treatment of HD and related neurodegenerative disorders involving protein misfolding and aggregation.

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Data Availability

Data will be made available by the corresponding author on request.

All experiments were conducted in accordance with the strict guidelines outlined by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA), Ministry of Environment and Forestry, Government of India, and were approved by the Institutional Animal Ethics Committee of the National Brain Research Centre (protocol number NBRC/IAEC/2019/154).

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Acknowledgements

We would like to sincerely thank Mr. Mahendra Kumar Singh for his technical assistance.

Funding

This work was supported by a common research grant from BRICS countries involving India (Department of Science and Technology, reference number DST/IMRCD/BRICS/Neurotherapy/2017) and Russia (The Russian Foundation for Basic Research, grant number 17–54-80006) as well as from the core grant of NBRC provided by Department of Biotechnology, Govt. of India.

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Authors and Affiliations

  1. Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon, 122 051, India

    Tripti Joshi, Vipendra Kumar & Nihar Ranjan Jana

  2. Institute of Cytology, Russian Academy of Sciences, 194064, St. Petersburg, Russia

    Elena V. Kaznacheyeva

  3. School of Bioscience, Indian Institute of Technology, Kharagpur, 721302, India

    Nihar Ranjan Jana

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  1. Tripti Joshi
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All authors contributed study conception and design. Experimentations were performed by Tripti Joshi and Vipendra Kumar; data were analyzed by Tripti Joshi and Nihar Ranjan Jana. The first draft of the manuscript was written by Nihar Ranjan Jana and all authors read, commented and approved the final manuscript.

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Joshi, T., Kumar, V., Kaznacheyeva, E.V. et al. Withaferin A Induces Heat Shock Response and Ameliorates Disease Progression in a Mouse Model of Huntington’s Disease. Mol Neurobiol 58, 3992–4006 (2021). https://doi.org/10.1007/s12035-021-02397-8

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