Polyglutamine fibrillogenesis: The pathway unfolds

Abstract

Nine neurodegenerative diseases are caused by expanding CAG repeats coding for polyglutamine (polyGln) (1–4). These include Huntington's disease, dentatorubral and pallidoluysian atrophy, several forms of spino-cerebellar ataxia, and spinal and bulbar muscular atrophy. Within the central nervous system, each disease has a distinctive pattern of degeneration, with considerable overlap among the diseases (5, 6). The genes containing CAG repeats show no homology to each other outside of the glutamine repeats, and most are genes of unknown function. Thus, speculation concerning pathogenesis has focused on the polyGln expansion itself. For all of these diseases, there is a threshold of repeat length that causes disease. This threshold varies somewhat among the different diseases, but is generally in the range of 35–45 consecutive glutamines. In all polyGln diseases, the age of disease onset is strongly correlated with polyGln length, so that above the threshold, a longer repeat results in an earlier age of onset. A pathological hallmark of these diseases is the aggregation of mutant polyGln protein, resulting in the formation of intranuclear inclusion bodies. In some of the diseases, inclusions have been observed in the cytoplasm, dendrites, and axonal processes. The inclusions are generally seen in affected areas of the brain (7, 8), though not limited to those neurons most likely to degenerate (9). Thus, whether inclusions are responsible for neurotoxicity has been controversial. Some studies have indicated a correlation between polyGln-containing inclusions and disease progression (10). However, in other studies, inclusion formation was dissociated from cytotoxicity (11, 12). In fact, inclusion formation may be, in part, a reflection of cellular protective mechanisms (13). Nevertheless, the inclusions are a useful marker for pathology and may provide clues to pathogenesis. Aggregation of mutant polyGln proteins can be observed biochemically using a filter trap assay (14, 15). Aggregation …