title: Mice lacking caspase-2 are protected from behavioral changes, but not pathology, in the YAC128 model of Huntington disease.
abstract: BACKGROUND
  Huntington Disease (HD) is a neurodegenerative disorder in which caspase activation and cleavage of substrates, including the huntingtin protein, has been invoked as a pathological mechanism. Specific changes in caspase-2 (casp2) activity have been suggested to contribute to the pathogenesis of HD, however unique casp2 cleavage substrates have remained elusive. We thus utilized mice completely lacking casp2 (casp2-/-) to examine the role played by casp2 in the progression of HD. This 'substrate agnostic' approach allows us to query the effect of casp2 on HD progression without pre-defining proteolytic substrates of interest.
  
  
  RESULTS
  YAC128 HD model mice lacking casp2 show protection from well-validated motor and cognitive features of HD, including performance on rotarod, swimming T-maze, pre-pulse inhibition, spontaneous alternation and locomotor tasks. However, the specific pathological features of the YAC128 mice including striatal volume loss and testicular degeneration are unaltered in mice lacking casp2. The application of high-resolution magnetic resonance imaging (MRI) techniques validates specific neuropathology in the YAC128 mice that is not altered by ablation of casp2.
  
  
  CONCLUSIONS
  The rescue of behavioral phenotypes in the absence of pathological improvement suggests that different pathways may be operative in the dysfunction of neural circuitry in HD leading to behavioral changes compared to the processes leading to cell death and volume loss. Inhibition of caspase-2 activity may be associated with symptomatic improvement in HD.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, V5Z 4H4, Canada. mrh@cmmt.ubc.ca.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Carroll
authors.forename: Amber L
authors.initials: AL
authors.lastname: Southwell
authors.forename: Rona K
authors.initials: RK
authors.lastname: Graham
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lerch
authors.forename: Dagmar E
authors.initials: DE
authors.lastname: Ehrnhoefer
authors.forename: Li-Ping
authors.initials: LP
authors.lastname: Cao
authors.forename: Wei-Ning
authors.initials: WN
authors.lastname: Zhang
authors.forename: Yu
authors.initials: Y
authors.lastname: Deng
authors.forename: Nagat
authors.initials: N
authors.lastname: Bissada
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden