Huntington's disease and dentatorubral-pallidoluysian atrophy: proteins, pathogenesis and pathology

Each of the glutamine repeat neurodegenerative diseases has a particular pattern of pathology largely restricted to the CNS. However, there is considerable overlap among the regions affected, suggesting that the diseases share pathogenic mechanisms, presumably involving the glutamine repeats. We focus on Huntington's disease (HD) and Dentatorubral-pallidoluysian atrophy (DRPLA) as models for this family of diseases, since they have striking similarities and also notable differences in their clinical features and pathology. We review the pattern of pathology in adult and juvenile onset cases. Despite selective pathology, the disease genes and their protein products (huntingtin and atrophin-1) are widely expressed. This presents a central problem for all the glutamine repeat diseases-how do widely expressed gene products give rise to restricted pathology? The pathogenic effects are believed to occur via a "gain of function" mechanism at the protein level. Mechanisms of cell death may include excitotoxicity, metabolic toxicity, apoptosis, and free radical stress. Emerging data indicate that huntingtin and atrophin-1 may have distinct protein interactions. The specific interaction partners may help explain the selective pathology of these diseases.