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Kerry Murphy & Mark Hirst"What can a mouse tell us about Huntington's disease: somatic mutation and altered dopaminergic function? "

Abstract :

This seminar will be a double act - Mark Hirst will focus on the molecular aspects of the 89Q line and Kerry Murphy will talk about the electrophysiology.
Transgenic mouse models for Huntington's disease have proved valuable tools for insights into many aspects of the human disease process. We will describe a novel mouse line derived from the commonly studied R6/1 mouse by a truncation of the transgenic (CAG)n triplet repeat sequence. This event truncated the transgenic CAG repeat from 116 to 89 triplets and gives rise to a mouse with a significantly later onset of motor and physical characteristics of disease.  Ours studies show that localised CAG expansion is extensive before phenotype development and the expanded gene is expressed. These data suggest that progressively expanding polyQ containing protein is likely to be present in neurons and is likely to influence cell function.  We are particularly interested in understanding how the phenotype of dopaminergic neurones changes with disease progression and will discuss how this may be influenced by cell autonomous polyQ interactions.

Selected publications

Recent Related Publications
Dallerac et al. Impaired long-term potentiation (LTP) in the prefrontal cortex of Huntington's disease mouse models: rescue by D1 dopamine receptor activation. Neurodegenerative Diseases 8, 230-9.
Vatsavayai et al. (2007) Progressive CAG expansion in the brain of a novel R6/1-89Q mouse model of Huntington' disease with delayed phenotypic onset. Brain Res. Bull. 72, 98-102.

Cummings et al. (2006) Aberrant cortical synaptic plasticity and dopaminergic dysfunction in a mouse model of Huntington's disease. Human Mol. Genet. 15, 2856-68.

Milnerwood et al. (2006) Early development of aberrant synaptic plasticity in a mouse model of Huntington's disease. Human Mol. Genet. 15, 1690-703.

Scientific focus :

Biography Dr Mark Hirst
After graduating in Biochemistry from Manchester University, I studied for a PhD with Prof David Porteous at the MRC in Edinburgh, graduating in 1988. I worked on fragile X syndrome with Prof Kay Davies in the IMM (University of Oxford), during which time we identified methylation and triplet expansion mutations in fragile X individuals and published the first molecular prenatal diagnosis case. Work continued on expanded triplet repeats, with expansions being identified at both the FRAXE and FRAXF fragile sites and also on identifying molecular pathways and processes involved in the expansion process. In 1999, I moved to the Open University, where work on triplet repeat instability continued and developed into a focus on molecular neurophysiology, in particular understanding the relationship between neural cell dysfunction and genetic changes in Huntington's disease. A novel variant of the R6/1 mouse line was identified and is now the central point of study of early events in Huntington's disease.

Biography Dr Kerry Murphy
My background as an electrophysiologist is in synaptic mechanisms that support learning and memory and I honed my craft working with Prof Tim Bliss FRS at the National Institute for Medical Research in London. Whilst in London I developed an interest in exploring how synaptic plasticity is affected by neurodegenerative diseases and used my move to the Open University in 2000 to establish a laboratory to study synaptic plasticity in a mouse model of Huntington's disease. Our studies have demonstrated that synaptic dysfunction is an early event in Huntington's disease mice and can be reversed by dopaminergic intervention.

Yoon Cho de l'INCIA