Huntingtin aggregates may not predict neuronal death in Huntington's disease

The mechanism by which polyglutamine expansion in Huntington's disease (HD) results in selective neuronal degeneration remains unclear. We previously reported that the immunohistochemical distribution of N-terminal huntingtin in HD does not correspond to the severity of neuropathology, such that sig nificantly greater numbers of huntingtin aggregates are present within the cortex than in the striatum. We now show a dissociation between huntingtin aggregation and the selective pattern of striatal neuron loss observed in H D. Aggregate formation was predominantly observed in spared interneurons, w ith few or no aggregates found within vulnerable spiny striatal neurons. Mu ltiple perikaryal aggregates were present in almost all cortical NADPH-diap horase neurons and in approximately 50% of the spared NADPH-diaphorase stri atal neurons from early grade HD cases. In severe grade HD patients, aggreg ates were more prominent as nuclear inclusions in NADPH-diaphorase neurons, with less perikaryal and neuropil aggregation. In contrast, nuclear or per ikaryal huntingtin aggregates were present in less than 4% of the vulnerabl e calbindin striatal neurons in all HD cases. These findings support the hy pothesis that polyglutamine aggregation may not be a predictor of cell loss . Rather than a harbinger of neuronal death, mutant huntingtin aggregation may be a cytoprotective mechanism against polyglutamine-induced neurotoxici ty.