Synaptic Dysfunction in Huntington’s Disease

Abstract:

Huntington’s disease (HD) is a progressive, inherited, neurodegenerative disorder characterised by movement abnormalities, cognitive impairments and emotional disturbance (Bates et al. 2002). The genetic mutation for HD is an unstable CAG repeat expansion in the HD gene (Huntington’s Disease Collaborative Research Group 1993). The HD gene codes for a protein named huntingtin, and the CAG repeat is translated to an expanded polyglutamine repeat in the disease protein. However, even though the genetic mutation was identified more than 15 years ago, it is still not known how it causes HD. Until recently, the prevailing hypothesis was that the clinical manifestations of HD were due to selective neuronal degeneration in the striatum and cortex. Nevertheless, there is a growing body of work supporting the idea that some of the earliest changes apparent in HD, in particular changes in personality, mood and cognitive performance, may arise as a consequence of ­synaptic dysfunction. Here, we discuss the idea that synaptic dysfunction (rather than frank cell loss) may underlie early symptoms in HD.