Recruitment of nonexpanded polyglutamine proteins to intranuclear aggregates in neuronal intranuclear hyaline inclusion disease

Recruitment of polygluramine-containing proteins into nuclear inclusions (N Is) was investigated in neuronal intranuclear hyaline inclusion disease (NI HID). Some polyglutamine-containing proteins, ataxin-2, ataxin-3, and TATA box binding protein (TBP), as well as unidentified proteins with expanded p olyglutamine tracts were recruited into NIs with different frequencies, Ata xin-3 was incorporated into most of the NIs and disappeared from its normal cytoplasmic localization, whereas only a small fraction of NIs contained a taxin-2 and TBP. The consistent presence of ataxin-3 in NIs could reflect a biological feature of wild-type ataxin-3, which is translocated into the n ucleus under pathological conditions and participates in the formation of a ggregates. Ataxin-2 also accumulated in the nucleus, but was not necessaril y incorporated into NIs, suggesting that transport of these cytoplasmic pro teins into the nucleus and their recruitment into NIs are not wholly explai ned by an interaction with a polyglutamine stretch and must be regulated in part by other mechanisms. The prevalence of ubiquitin-immunopositive NIs w as inversely correlated to neuronal loss in all cases examined. This correl ation could be explained if NI formation is a protective mechanism involvin g the ubiquitin-proteasome pathway. This hypothesis is supported by the fin ding that the polyglutamine epitope in the center of NIs was surrounded by ubiquitin.