Azadiradione ameliorates polyglutamine expansion disease in Drosophila by potentiating DNA binding activity of heat shock factor 1.
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.
Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.|Department of Pharmaceutical Technology, Pharmacognosy and Phytotherapy Laboratory, Jadavpur University, Jadavpur, West Bengal, India.
Vinod K
VK
Nelson
Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
Asif
A
Ali
Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
Naibedya
N
Dutta
Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
Suvranil
S
Ghosh
Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
Manas
M
Jana
Dr. B. C. Guha Center for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, West Bengal, India.
Arnab
A
Ganguli
Cellecta Inc, Mountain View, California, United States of America.
Andrei
A
Komarov
Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
Soumyadip
S
Paul
Department of Zoology, Cytogenetics Laboratory, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Vibha
V
Dwivedi
Department of Biophysics, Bose Institute, Kolkata, West Bengal, India.
Subhrangsu
S
Chatterjee
Cellular and Molecular Neuroscience Laboratory, National Brain Research Institute, Manesar, Gurgaon, Haryana, India.
Nihar R
NR
Jana
Department of Zoology, Cytogenetics Laboratory, Banaras Hindu University, Varanasi, Uttar Pradesh, India.
Subhash C
SC
Lakhotia
Dr. B. C. Guha Center for Genetic Engineering and Biotechnology, University of Calcutta, Kolkata, West Bengal, India.
Gopal
G
Chakrabarti
Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
Anup K
AK
Misra
Department of Pharmaceutical Technology, Pharmacognosy and Phytotherapy Laboratory, Jadavpur University, Jadavpur, West Bengal, India.
Subhash C
SC
Mandal
Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India.
Mahadeb
M
Pal
D000818:Animals; D031601:Azadirachta / Q000737:chemistry; D004247:DNA / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D045325:HCT116 Cells; D057809:HEK293 Cells; D000076249:Heat Shock Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D036701:Limonins / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D010455:Peptides / Q000378:metabolism*; D010936:Plant Extracts / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D066263:Protein Aggregation, Pathological; D011485:Protein Binding; D012639:Seeds; D013997:Time Factors; D014162:Transfection
D029721:Drosophila Proteins; C000619706:HSF1 protein, human; D000076249:Heat Shock Transcription Factors; C053134:Hsf protein, Drosophila; D036701:Limonins; D018696:Neuroprotective Agents; D010455:Peptides; D010936:Plant Extracts; C479321:azadiradione; C097188:polyglutamine; D004247:DNA
Gerotarget; HSF1; azadiradione; heat shock factor 1; neurodegenerative diseases; small molecule