Ataxin-3 is translocated into the nucleus for the formation of intranuclear inclusions in normal and Machado-Joseph disease brains.

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is one of the dominantly inherited cerebellar ataxias. The gene responsible for the disease, a novel gene of unknown function, encodes ataxin-3 containing a polyglutamine stretch. Although it has been known that ataxin-3 is incorporated into neuronal intranuclear inclusions (NIIs) in neurons of affected regions, the relationship between NII formation and neuronal degeneration still remains uncertain. In the present study we show two different conditions in which ataxin-3 is recruited into the nucleus and suggest a process to form nuclear inclusions. In normal brains, wild-type ataxin-3 localizes within the ubiquitin-positive nuclear inclusion, the Marinesco body, indicating that ataxin-3 is recruited into the nuclear inclusion even in the absence of pathologically expanded polyglutamine. In MJD/SCA3 brains, immunohistochemical analyses with anti-ataxin-3 antibody, anti-ubiquitin antibody, and monoclonal antibody 1C2 known to recognize expanded polyglutamine revealed differences in frequency and in diameter among NIIs recognized by each antibody. These results were confirmed in the same inclusions by double immunofluorescent staining, suggesting that expanded ataxin-3 forms a core, thereby recruiting wild-type ataxin-3 into the nucleus around the core portion, and then followed by activation of the ubiquitin/ATP-dependent pathway. Recruitment of ataxin-3 into the nucleus and formation of nuclear inclusion under two different conditions suggest that ataxin-3 may be translocated into the nucleus under certain conditions stressful on neuronal cells such as aging and polyglutamine neurotoxicity.