Oncotarget

Research Papers: Gerotarget (Focus on Aging):

Azadiradione ameliorates polyglutamine expansion disease in Drosophila by potentiating DNA binding activity of heat shock factor 1

Vinod K. Nelson _, Asif Ali, Naibedya Dutta, Suvranil Ghosh, Manas Jana, Arnab Ganguli, Andrei Komarov, Soumyadip Paul, Vibha Dwivedi, Subhrangsu Chatterjee, Nihar R. Jana, Subhash C. Lakhotia, Gopal Chakrabarti, Anup K. Misra, Subhash C. Mandal and Mahadeb Pal

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Oncotarget. 2016; 7:78281-78296. https://doi.org/10.18632/oncotarget.12930

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Abstract

Vinod K. Nelson1,7,*, Asif Ali1,*, Naibedya Dutta1, Suvranil Ghosh1, Manas Jana1, Arnab Ganguli2, Andrei Komarov3, Soumyadip Paul1, Vibha Dwivedi4, Subhrangsu Chatterjee5, Nihar R. Jana6, Subhash C. Lakhotia4, Gopal Chakrabarti2, Anup K. Misra1, Subhash C. Mandal7 and Mahadeb Pal1

1 Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India

2 Dr. B. C. Guha Center for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, West Bengal, India

3 Cellecta Inc, Mountain View, California, United States of America

4 Department of Zoology, Cytogenetics Laboratory, Banaras Hindu University, Varanasi, Uttar Pradesh, India

5 Department of Biophysics, Bose Institute, Kolkata, West Bengal, India

6 Cellular and Molecular Neuroscience Laboratory, National Brain Research Institute, Manesar, Gurgaon, Haryana, India

7 Department of Pharmaceutical Technology, Pharmacognosy and Phytotherapy Laboratory, Jadavpur University, Jadavpur, West Bengal, India

* These authors have contributed equally to this work

Correspondence to:

Mahadeb Pal, email:

Keywords: heat shock factor 1, HSF1, neurodegenerative diseases, small molecule, azadiradione, Gerotarget

Received: June 27, 2016 Accepted: August 21, 2016 Published: October 26, 2016

Abstract

Aggregation of proteins with the expansion of polyglutamine tracts in the brain underlies progressive genetic neurodegenerative diseases (NDs) like Huntington’s disease and spinocerebellar ataxias (SCA). An insensitive cellular proteotoxic stress response to non-native protein oligomers is common in such conditions. Indeed, upregulation of heat shock factor 1 (HSF1) function and its target protein chaperone expression has shown promising results in animal models of NDs. Using an HSF1 sensitive cell based reporter screening, we have isolated azadiradione (AZD) from the methanolic extract of seeds of Azadirachta indica, a plant known for its multifarious medicinal properties. We show that AZD ameliorates toxicity due to protein aggregation in cell and fly models of polyglutamine expansion diseases to a great extent. All these effects are correlated with activation of HSF1 function and expression of its target protein chaperone genes. Notably, HSF1 activation by AZD is independent of cellular HSP90 or proteasome function. Furthermore, we show that AZD directly interacts with purified human HSF1 with high specificity, and facilitates binding of HSF1 to its recognition sequence with higher affinity. These unique findings qualify AZD as an ideal lead molecule for consideration for drug development against NDs that affect millions worldwide.


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