title: Topoisomerase 1 inhibitor topotecan delays the disease progression in a mouse model of Huntington's disease.
abstract: Huntington's disease (HD) is a dominantly inherited progressive neurodegenerative disorder caused by the accumulation of polyglutamine expanded mutant huntingtin as inclusion bodies primarily in the brain. After the discovery of the HD gene, considerable progress has been made in understanding the disease pathogenesis and multiple drug targets have been identified, even though currently there is no effective therapy. Here, we demonstrate that the treatment of topotecan, a brain-penetrating topoisomerase 1 inhibitor, to HD transgenic mouse considerably improved its motor behavioural abnormalities along with a significant extension of lifespan. Improvement of behavioural deficits are accompanied with the significant rescue of their progressively decreased body weight, brain weight and striatal volume. Interestingly, topotecan treatment also significantly reduced insoluble mutant huntingtin load in the HD mouse brain. Finally, we show that topotecan treatment to HD mouse not only inhibits the expression of transgenic mutant huntingtin, but also at the same time induces the expression of Ube3a, an ubiquitin ligase linked to the clearance of mutant huntingtin. These findings suggest that topotecan could be a potential therapeutic molecule to delay the progression of HD.
authors.forename: Shashi
authors.initials: S
authors.lastname: Shekhar
authors.forename: Naman
authors.initials: N
authors.lastname: Vatsa
authors.forename: Vipendra
authors.initials: V
authors.lastname: Kumar
authors.forename: Brijesh Kumar
authors.initials: BK
authors.lastname: Singh
authors.forename: Imran
authors.initials: I
authors.lastname: Jamal
authors.forename: Ankit
authors.initials: A
authors.lastname: Sharma
authors.forename: Nihar Ranjan
authors.initials: NR
authors.lastname: Jana
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D004264:DNA Topoisomerases, Type I / Q000235:genetics; D004195:Disease Models, Animal; D018450:Disease Progression; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D000071058:Huntingtin Protein / Q000096:biosynthesis / Q000235:genetics*; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D017072:Neostriatum / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D059004:Topoisomerase I Inhibitors / Q000008:administration & dosage*; D019772:Topotecan / Q000008:administration & dosage*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: D000071058:Huntingtin Protein; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases; D004264:DNA Topoisomerases, Type I