Neuronal nuclear alterations in dentatorubral-pallidoluysian atrophy: ultrastructural and morphometric studies of the cerebellar granule cells

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neuro degenerative disease caused by a. CAG repeat expansion, resulting in ubiqui tinated inclusions and diffuse accumulation of mutant atrophin-1 in the neu ronal nuclei in many regions of the central nervous system. In the cerebell ar cortex, such nuclear abnormalities occur in the granule cells. In the pr esent study, we performed ultrastructural and morphometric analyses on the nuclei of the cerebellar granule cells from eight patients with DRPLA (four with juvenile-onset disease and four with adult-onset disease) in an attem pt to obtain further insight into the neuronal nuclear alterations that occ ur in CAG-repeat diseases. Ultrastructurally, all patients had intranuclear filamentous inclusions (NIIs, neuronal intranuclear inclusions) and nuclea r membrane indentations (NMIs) in some of their granule cells, and chromati n tended to be sparse in the nucleoplasm of the affected nuclei. No such ch anges were observed in the granule cells of four control subjects. In all p atients there was an association between NIIs and NMIs, and nuclei with NII s and/or NMIs were larger than those without such changes. However, the nuc lear enlargement was not due solely to the NIIs - even nuclei without NIIs or NMIs were larger in the patients than in the controls. In the DRPLA pati ents, there was a significant inverse correlation between the cross-section al area of the nuclei and the disease duration. These findings indicate tha t Mis and NMIs are features in the disease and occur in association with ea ch other, and that nuclear enlargement - the degree of which may decrease w ith time after onset of the illness - is a more prevalent abnormality than the formation of NIIs or NMIs. (C) 2001 Elsevier Science B.V. All rights re served.