Progressive formation of inclusions in the striatum and hippocampus of mice transgenic for the human Huntington's disease mutation

The significance of neuronal intranuclear inclusions (NIIs) and extranuclea r inclusions (ENNIs) in the brains of patients with polyglutamine repeat di seases and transgenic mice modelling these diseases is hotly debated. We ex amined inclusions in the brains of mice transgenic for the human Huntington 's disease mutation and found that their size, number and location varied m arkedly with age and neuronal phenotype. In striatum and hippocampus partic ularly, inclusions appeared at different times in different cell types. Fur ther, the mechanism of formation of inclusions appears to be complex, with several distinct phases. These include a precipitous formation of NIIs foll owed by NII growth, and the concomitant formation ENNIs. While the timing o f appearance of NIIs and ENNIs parallels the cognitive and motor decline of the mice, the precise role of NIIs and ENNIs is unknown. It has been vario usly suggested that NIIs may be deleterious, benign or beneficial. However, our data allows the possibility that each of these is possible, and sugges t also that the role of inclusions changes with time. The precipitous forma tion of NIIs may play a protective role by removing polyglutamine, while th e subsequent growth of NIIs may be deleterious, since it would allow other proteins to be sequestered into inclusions. The formation of ENNIs in neuri tes and synapses is also more likely to have deleterious than beneficial co nsequences for a cell. Thus, our study suggests that the relationship betwe en inclusion formation and neurological dysfunction depends not only upon t he phenotype of the neurons involved, but also upon the molecular compositi on and the subcellular localisation of the inclusions.