Individuals carrying the HD gene express mutant huntingtin in neurons throughout the brain, along with normal huntingtin expressed from the normal copy of the gene on the other chromosome. The brain regions that show the most severe loss of neurons in HD are the striatum and the cortex. What causes greater cell death in striatal and cortical cells than in other neurons is an enigma. Striatal cells are known to be particularly sensitive to metabolic stress and to injury by excitatory amino acids. These factors have long been suspected to contribute to HD pathology, but how they are influenced by mutant huntingtin is unclear.
Peptides consisting solely of glutamine residues can form insoluble complexes.
This led to speculation that mutant huntingtin, and other disease proteins with expanded polyglutamine regions, could aggregate in the brain. Indeed, studies subsequently showed that the mutant huntingtin with an expanded N-terminal polyglutamine region aggregates in the nucleus and in the cytoplasm of the cell. Aggregates also form in axons, which degenerate into what are now called dystrophic neurites. The aggregated mutant huntingtin colocalizes in complexes with ubiquitin, a protein that is known to assist in the removal of abnormal or misfolded proteins. Ubiquitin is often associated with a protein that is targeted for destruction by the proteasome, a cellular machine that degrades proteins.