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M07 Examining Conditional Caspase-6 Deficiency As A Therapeutic In Huntington Disease
  1. S Ladha,
  2. Y Deng,
  3. BKY Wong,
  4. MR Hayden
  1. Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, Canada

Abstract

Background Huntington disease (HD) is an autosomal dominant neurodegenerative disorder characterised by motor, cognitive, and psychiatric symptoms. HD is caused by a CAG repeat expansion in the huntingtin (HTT) gene resulting in the production of mutant huntingtin (mHTT). Caspase-6 (C6) is a protease that plays a central role in programmed cell death and has recently been implicated in several neurodegenerative diseases. Increased C6 activation is observed in human HD brains and in mouse models of HD, and genetic or peptide inhibition of C6 activity protects neurons from degeneration. C6 is one of several proteases that cleaves mHTT, and our lab has previously demonstrated that preventing C6-mediated cleavage of mHTT at the 586 amino acid site preserves striatal volume and rescues cognitive and motor deficits in the YAC128 mouse model of HD. These data point to an essential role for C6 in the pathogenesis of HD and provide a rationale for the inhibition of C6 as a therapeutic approach.

Aim The goal of this study is to investigate the effects of genetically knocking out C6 in adulthood on the phenotype of the YAC128 mouse model of HD.

Method Excision of the C6 gene in YAC128 mice will be carried out using the Cre/loxP system and by administering tamoxifen at 6 weeks of age. Treated mice will be examined for behavioural, neuropathological and biochemical endpoints.

Results After extensive optimisation of tamoxifen administration, a treatment protocol was established to enable adequate excision of C6 in the brain. Mice have received 19 consecutive days of IP injections at 100mg/kg to induce excision and treated mice will be examined for behavioural, neuropathological and biochemical endpoints.

Conclusions Results from this study will provide insight into the effect of adult C6 inhibition on HD pathogenesis and will further validate C6 as a therapeutic target in HD.

KeyWords
  • caspase-6
  • proteolysis
  • YAC128 mouse model

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