Huntington’s Disease Pathogenesis: Mechanisms and Pathways

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. HD displays the genetic feature of anticipation, defined as earlier disease onset and more rapid disease progression in successive generations of a pedigree segregating the disease gene. This feature was an important clue for discovery of the causal mutation, as a trinucleotide repeat expansion encoding an elongated glutamine tract in the htt protein was determined to be responsible for HD in 1993, and a relationship between the length of the expanded glutamine tract and the severity of the HD phenotype was uncovered at that time [1]. HD is one of nine inherited neurodegenerative disorders caused by CAG trinucleotide repeats that expand to produce disease by encoding elongated polyQ tracts in their respective protein products. Included in this CAG/polyQ repeat disease class are spinal and bulbar muscular atrophy (SBMA), dentatorubral-pallidoluysian atrophy (DRPLA), and six forms of spinocerebellar ataxia (SCA1, SCA2, SCA3, SCA6, SCA7, and SCA17) [2]. Based on work done on all these disorders, investigators have learned that once glutamine tracts exceed the mid-30s, the polyQ tract adopts a novel conformation that is pathogenic. An antipolyQ antibody (1C2) can specifically detect this structural transformation, as it will only bind to disease-length polyQ tracts from patients with different polyQ diseases [3]. The transition of polyQ-expanded proteins into this misfolded conformer is the crux of the molecular pathology in these disorders. Once in this conformation, however, it is unclear how polyQ tract expansions mediate the patterns of neuronal cell loss seen in each disease, as most of the polyQ disease gene products show overlapping patterns of expression within the central nervous system (CNS) but restricted pathology. In the case of HD, molecular explanations for disease pathogenesis must account for the selective vulnerability of the medium spiny neurons of the striatum and certain neuron subsets in the cortex.