Neurotoxicity in huntington disease

Abstract

Huntington Disease (HD) is an autosomal dominant, progressive, neurodegenerative disorder, due to abnormal CAG expansion in the Chromosome 4 Huntingtin (HTT) gene. Typical age of onset is in the 30s-40s, and symptoms include involuntary movements, cognitive/behavioural symptoms and psychiatric disorders. As a monogenic disorder, the aetiology of HD is well established - however our understanding of the pathogenesis of HD is still evolving. In particular, mutation in the HTT gene confers neurotoxicity on multiple levels, ranging from the genetic/protein level, intracellular level, intercellular level, to the end-organ level. On a genetic/protein level, a HTT mutation is associated with toxic gain of function, loss of normal function and altered transcription of other genes. On an intracellular level, it is associated with mitochondrial dysfunction and impaired cytoskeleton/intra-cellular trafficking. On an intercellular level, it is associated with impaired synaptic transmission, excitoxicity and inflammation. On an organ level, both the brain and peripheral tissues are affected. We will review each of these areas in this article.