INTRANUCLEAR NEURONAL INCLUSIONS IN HUNTINGTONS-DISEASE AND DENTATORUBRAL AND PALLIDOLUYSIAN ATROPHY - CORRELATION BETWEEN THE DENSITY OF INCLUSIONS AND IT15 CAG TRIPLET REPEAT LENGTH

Huntington's disease (HD) is caused by CAG triplet repeat expansion in IT15 which leads to polyglutamine stretches in the HD protein product , huntingtin. The pathological hallmark of HD is the degeneration of s ubsets of neurons, primarily those in the striatum and neocortex. Spec ific morphological markers of affected cells have not been identified in patients with HD, although a unique intranuclear inclusion was rece ntly reported in neurons of transgenic animals expressing a construct encoding the N-terminal part (including the glutamine repeat) of hunti ngtin (Davies ef at, 1997). In order to understand the importance of t his finding, we sought for comparable nuclear abnormalities in autopsy material from patients with HD. In all 20 HD cases examined, anti-ubi quitin and N-terminal huntingtin antibodies identified intranuclear in clusions in neurons and the frequency of these lesions correlated with the length of the CAG repeat in IT15. In addition, examination of mat erial from the related HD-like triplet repeat disorder, dentatorubral and pallidoluysian atrophy, also revealed intranuclear neuronal inclus ions. These findings suggest that intranuclear inclusions containing p rotein aggregates may be a common feature of the pathogenesis of gluta mine repeat neurodegenerative disorders. (C) 1998 Academic Press.