Neuronal intranuclear hyaline inclusion disease with polyglutamine-immunoreactive inclusions

Neuronal intranuclear hyaline inclusion disease (NIHID) is a group of neuro degenerative disorders characterized by the presence of intranuclear inclus ions in neurons (NIs). We report here clinicopathological findings of a 25- year-old female patient who died after 13 years of a clinical course charac terized by progressive gait disturbance and movement disorders. Histologica l examination revealed widespread NIs with neuronal loss in restricted regi ons; neuronal loss was severe in the subthalamic nucleus, internal pallidum , substantia nigra, Edinger-Westphal nucleus and Purkinje cell layer. Quant ification of the NIs combined with a graded evaluation of neuronal loss rev ealed an overall tendency for more severe neuronal loss to be accompanied b y a lower frequency of NIs. A morphological similarity to the nuclear inclu sions recently identified in several CAG repeat diseases prompted us to exa mine the immunolocalization of ubiquitin and expanded polyglutamine stretch es, which demonstrated the presence of ubiquitin at the periphery of most N Is. An expanded polyglutamine stretch was seen in the center of limited num ber of NIs. These findings indicate that abnormal fragments such as expande d polyglutamine regions are incorporated into the inclusion, aggregated in its center, and thereby metabolized by a ubiquitin-dependent proteolytic pa thway. Although it remains to be elucidated how the formation of NIs is rel ated to neuronal degeneration, our findings suggest that NIs are formed in the process of sequestering or degrading abnormal protein fragments and for mation of NIs may not be immediately toxic to neurons.