Azadiradione Restores Protein Quality Control and Ameliorates the Disease Pathogenesis in a Mouse Model of Huntington’s Disease
Huntington’s disease (HD) is an autosomal dominantly inherited neurodegenerative disorder caused by expansion of CAG repeats in the coding area of huntingtin gene. In the HD brain, mutant huntingtin protein goes through proteolysis, and its amino-terminal portion consisting of polyglutamine repeats accumulate as inclusions that result in progressive impairment of cellular protein quality control system. Here, we demonstrate that partial rescue of the defective protein quality control in HD model mouse by azadiradione (a bioactive limonoids found in the seed of Azadirachta indica) could potentially improve the disease pathology. Prolonged treatment of azadiradione to HD mice significantly improved the progressive deterioration in body weight, motor functioning along with extension of lifespan. Azadiradione-treated HD mice brain also exhibited considerable decrease in mutant huntingtin aggregates load and improvement of striatal pathology in comparison with age-matched saline-treated HD controls. Biochemical analysis further revealed upregulation and activation of not only HSF1 (master regulator of protein folding) but also Ube3a (an ubiquitin ligase involved in the clearance of mutant huntingtin) in azadiradione-treated mice. Our results indicate that azadiradione-mediated enhanced folding and clearance of mutant huntingtin might underlie improved disease pathology in HD mice and suggests that it could be a potential therapeutic molecule to delay the progression of HD.
KeywordsHuntington’s disease Azadiradione HSF1 Ube3a Proteostasis
The authors would like to sincerely thank Mr. Ankit Sharma and Mr. Mahendra Kumar Singh for their technical support.
This work was supported by the core funding of the National Brain Research Centre (under Department of Biotechnology, Government of India). NRJ is a recipient of TATA Innovation Fellowship from Department of Biotechnology, Government of India (BT/HRD/35/01/03/2013).
Compliance with Ethical Standards
All experiments were conducted according to the strict guideline proposed 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/2017/120).
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