The Study of Two Strategies for Decreasing Mutant Huntingtin: Degradation by Puromycin SensitiveAminoPeptidase and RNA Interference: A Dissertation

摘要: Huntington’s disease (HD) is a fatal neurodegenerative caused by CAG repeat expansion in exon 1 of the huntingtin gene, resulting an expanded polyglutamine (polyQ) protein. Patients receive symptomatic treatment for motor, emotional, and cognitive impairments; however, there no to slow progression disease, with death occurring 15-20 years after diagnosis. Mutant protein interferes multiple cellular processes leading dysfunction neuronal loss. Due complexity mutant toxicity, many approaches treating each effect are being investigated. Unfortunately, addressing one cause toxicity might not result protection from other toxic insults, necessitating combination treatments HD patients. Ideally, single therapy targeting mRNA or could prevent all downstream toxicities huntingtin. In this work, I used animal models investigate potential therapeutic target decreasing protein, apply bioluminescent imaging RNA interference silence sites. The enzyme puromycin sensitive aminopeptidase (PSA) has unique property degrading polyQ peptides been implicated degradation study, we looked decreased PSA on pathology behavior mouse model disease. To achieve this, crossed mice functional allele inactivated allele. We found that heterozygous develop greater number pathological inclusion bodies, representing accumulation neurons.