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 po lyglutamine stretch. Although it has been known that ataxin-3 is incorporat ed into neuronal intranuclear inclusions (NIIs) in neurons of affected regi ons, the relationship between NII formation and neuronal degeneration still remains uncertain. In the present study we show two different conditions i n which ataxin-3 is recruited into the nucleus and suggest a process to for m nuclear inclusions. In normal brains, wild-type ataxin-3 localizes within the ubiquitin-positive nuclear inclusion, the Marinesco body, indicating t hat ataxin-3 is recruited into the nuclear inclusion even in the absence of pathologically expanded polyglutamine. In MJD/SCA3 brains, immunohistochem ical analyses with anti-ataxin-3 antibody, anti-ubiquitin antibody, and mon oclonal antibody 1C2 known to recognize expanded polyglutamine revealed dif ferences in frequency and in diameter among NIIs recognized by each antibod y. These results were confirmed in the same inclusions by double immunofluo rescent staining, suggesting that expanded ataxin-3 forms a core, thereby r ecruiting wild-type ataxin-3 into the nucleus around the core portion, and then followed by activation of the ubiquitin/ATP-dependent pathway. Recruit ment 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. (C) 2000 Academic Press.