The role of caspase-2 in the progression of Huntington disease in the YAC128 mouse

• Main Author: Carroll, Jeffrey Bryan
• Language: English
• Published: University of British Columbia 2010
• Online Access: http://hdl.handle.net/2429/27744

Huntington Disease (HD) is a neurodegenerative disorder caused by expansion of a poly-glutamine tract in the huntingtin (htt) protein. Poly-glutamine (polyQ) expansion of huntingtin leads to inevitable onset of affective, cognitive, motor symptoms and eventual death. Loss of neurons in specific regions of the brain underlies the development of symptoms in HD, and this loss has been shown to involve activation of caspase enzymes. The genetically faithful YAC128 mouse model of HD is an excellent system for the analysis of moderators of pathology, as a large suite of affective, cognitive, motor and neuropathological measures have been validated. We have applied advanced magnetic resonance imaging (MRI) techniques to the YAC128 mouse to define the natural history of neuropathology with great precision. This precision enables the understanding that pathology in the YAC128 is spatiotemporally dynamic, and establishes a toolkit of cross-sectional pathology markers with fidelity to the human disease. Caspase-2 (casp2) is a cysteinyl protease that has been implicated in the pathology of neurodegenerative conditions including excitotoxicity, ischemia, Alzheimer’s and Huntington disease. However, no interventional in vivo evidence unequivocally links casp2 to HD pathology. Casp2-/- mice are available to study the role played by casp2 in HD pathology. Careful longitudinal characterization of phenotypes in the casp2-/- mice is crucial for understanding the limitations of therapies targeting this enzyme, as well as deeper understanding the biology of casp2. We have therefore examined a number of parameters in aging mice, and discovered a large number of undocumented alterations, primarily metabolic in nature. Casp2-/- mice fail to gain fat mass due to altered basal metabolism and feeding behavior. They also have pathological alterations in the liver and hypothalamus that may underlie these changes. We have used mice lacking casp2 bred to the YAC128 model of HD to investigate the role played by caspase-2 in HD pathology. Mice lacking casp2 are protected from a number of behavioral and cognitive phenotypes of HD, while the neuropathology observed is unaltered by expression of casp2. This suggests a novel role for casp2 in neuronal function.