SUMOylation substrates in neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disorder characterized pathologically by the presence of ubiquitinated intranuclear inclusions (NII) in neuronal cells. We demonstrate that NIIs in both sporadic and familial NIID contained the small ubiquitin modifier-1 (SUMO-1) and the SUMOylation substrates promyelocytic leukaemia protein (PML) and histone deacetylase 4 (HDAC4). Both PML and SUMO-1 are major components of nuclear bodies (NBs), suggesting that the NIIs in NIID, as well as the intranuclear inclusions in polyglutamine diseases, might derive from these intranuclear functional domains that serve as sites for ubiquitin-related protein degradation. HDAC4 was also a major component of the NIIs. HDACs are transcriptional corepressors that regulate histone remodelling, and NBs are thought to be sites at which the level of histone acetylation is controlled. The presence of PML, SUMO-1 and HDAC4 in NIIs suggests that transcriptional activity regulated by histone acetylation might contribute to the disease process in NIID. In addition, we showed that another SUMOylation substrate, RanGAP1 is associated with NIIs only in the familial NIID patient. This might be explained by different pathogenetic mechanisms underlying subcategories of NIID, which is very heterogeneous.