Novel therapeutic targets for Huntington's disease

Huntington's disease (HD) is a fatal autosomal-dominant disorder involving progressive motor, cognitive and psychiatric symptoms. HD is one of a large family of neurodegenerative diseases caused by a trinucleotide (CAG) repeat mutation, encoding an expanded tract of glutamines in the disease protein. HD was one of the first neurological disorders for which accurate transgenic models were created, allowing mechanisms of pathogenesis to be explored at molecular, cellular and behavioural levels. In the last decade, the understanding of molecular and cellular changes which occur in HD prior to onset of symptoms, and at early and late stages of disease progression, has been greatly expanded. A wide range of potential molecular targets for therapeutic intervention have been identified, associated with a variety of cellular processes including gene transcription, protein trafficking, protein degradation, protein-protein interactions, glutamatergic synaptic transmission, presynaptic signalling, postsynaptic signalling, synaptic plasticity, dopaminergic and neurotrophic modulation of synaptic function, experience-dependent neurogenesis, mitochondrial function and oxidative metabolism. Presymptomatic testing for the HD gene mutation necessitates future development of novel therapeutics aimed at delaying onset of symptoms, as well as slowing or reversing disease progression.