Huntington’s disease (HD) is a late onset neurodegenerative disease with no known cure.  The main symptoms of this debilitating condition are uncontrolled writhing movements, cognitive decline and altered psychological behaviour.  These symptoms reflect neuronal death especially in the striatum and cortex of HD sufferers.  HD is an autosomal dominant inherited disorder caused by mutation of a single gene, huntingtin.  The unaffected version of the gene has 10-26 copies of the trinucleotide repeat CAG (coding for glutamine) and affected individuals have an expansion of this region with at least 40 copies.  The resulting huntingtin protein has an expanded stretch of polyglutamine residues altering the conformation, structure and binding properties of this protein, potentially leading to altered function and neuronal toxicity.   

My research uses a knock-in mouse model of HD (Q140) which expresses the expanded form of the huntingtin protein with approximately 140 repeats.  We culture hippocampal, striatal, cortical and cerebellar granule neurons from these mice and investigate the presynaptic mechanisms involved in neurotransmitter release and synaptic vesicle recycling.  We do this through biochemical assays, fluorescent imaging of real-time vesicle recycling and electron microscopy.  My research also uses induced pluripotent stem cells from patients with HD.  We are currently characterising these cells and will be using them in parallel with the mouse cultures to investigate presynaptic dysfunction in a human model of HD.  Together, the findings from these models will provide important insights into the cause of neuronal degeneration in this devastating condition and potentially provide information which is applicable to neurodegeneration more broadly.