Huntington's disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein

Intranuclear inclusion bodies are a shared pathological feature of Huntingt on's disease (HD) and its transgenic mouse model. Using a panel of antibodi es spanning the entire huntingtin molecule, we have investigated the patter n of immunoreactivity within the intranuclear inclusions in the frontal cor tex and striatum of patients with HD, The intranuclear inclusions reacted w ith anti-ubiquitin and antibodies against the N-terminal portion of hunting tin (CAG53b, HP1), but not with HD1 and the 1C2 antibodies that detect the expanded polyglutamine tract nor the more C-terminal antibodies. However, t he 1C2, HP1, CAG53b, and HD1 antibodies detected granular cytoplasmic depos its in cortical and striatal neurons that also contained intranuclear N-ter minal huntingtin immunoreactivity, These data show a differential intracell ular location of truncated huntingtin in the HD brain. Both the cytoplasmic and the nuclear aggregates of the protein fragments could be neurotoxic. T he frequency of the cortical intranuclear inclusions correlated with the si ze of CAG; expansion and was inversely related to the age at onset and deat h. No such correlations were detected for the striatum, which most likely r eflects a more advanced neuronal loss accrued by the time of death, (C) 199 9 Academic Press.