Azadiradione Restores Protein Quality Control and Ameliorates the Disease Pathogenesis in a Mouse Model of Huntington’s Disease

• Published in: Molecular neurobiology 2018-08, Vol.55 (8), p.6337-6346
• Main Authors: Singh, Brijesh Kumar, Vatsa, Naman, Nelson, Vinod K., Kumar, Vipendra, Kumar, Shashi Shekhar, Mandal, Subhash C., Pal, Mahadeb, Jana, Nihar Ranjan
• Format: Article
• Language: English
• Subjects: Animals; Atrophy; Auditory defects; Biochemical analysis; Biomedical and Life Sciences; Biomedicine; Body weight; Brain; Cell Biology; Disease Models, Animal; Disease Progression; Dopamine and cAMP-Regulated Phosphoprotein 32 - metabolism; Folding; Heat Shock Transcription Factors - metabolism; HSF1 protein; Huntingtin; Huntingtin Protein - metabolism; Huntington Disease - drug therapy; Huntington Disease - pathology; Huntington Disease - physiopathology; Huntington's disease; Huntingtons disease; Life span; Limonins - administration & dosage; Limonins - pharmacology; Limonins - therapeutic use; Longevity; Medical treatment; Mice; Mice, Transgenic; Models, Biological; Motor Activity - drug effects; Mutant Proteins - metabolism; Neostriatum; Neostriatum - drug effects; Neostriatum - metabolism; Neostriatum - pathology; Neostriatum - physiopathology; Neural coding; Neurobiology; Neurodegenerative diseases; Neurology; Neurosciences; Pathology; Polyglutamine; Protein Aggregates - drug effects; Protein folding; Proteins; Proteolysis; Quality Control; Trinucleotide repeat diseases; Trinucleotide repeats; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - metabolism; Up-Regulation
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-017-0853-3

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.