Huntington’s Disease Pathogenesis: Mechanisms and Pathways

Abstract

The discovery in 1993 of the gene responsible for Huntington’s disease (HD) represented a crucial turning point in the HD research field. At the time of the discovery, no one could predict that HD would belong to a large class of inherited neurological diseases all caused by the same type of genetic mutation (i.e., polyglutamine [polyQ] expansion) or that the mechanistic basis of HD (i.e., protein misfolding) would emerge as a common theme linking together all the major neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and the prion diseases. The study of how the mutant HD gene product, an unusually large 3,144 amino acid protein (huntingtin [htt]) with few recognizable motifs or obvious functional domains that results in the degeneration and death of neurons in the striatum and cortex, has been an enormous undertaking. Indeed, a PubMed search using the term “huntingtin” yields 1,124 hits at the time of writing this chapter. Suffice it to say that dozens of theories of pathogenesis have been proposed and studied. The goal of this chapter will be to present some of the most enduring lines of investigation, with an emphasis on the latest developments, and to highlight emerging notions likely to drive basic research on HD in the future.