Nucleocytoplasmic transport of huntingtin and Huntington's disease

One historic characteristic of Huntington's disease (HD), which affected brains in both patient studies and HD mouse models was the detection of elevated levels of huntingtin protein fragments (NNI, neuronal nuclear inclusions) in the nuclei of several neuronal sub-types. This nuclear localization of mutant huntingtin fragments has been implicated as a potential gain of function for polyglutamine expanded huntingtin and may indicate the underlying molecular mechanism of pathology in HD. The nuclear localization of huntingtin fragments also indicates one downstream effect of polyglutamine-induced proteolysis. The mechanism of nuclear entry and the role of proteolysis of huntingtin are not clearly understood and are controversial with respect to the role of polyglutamine. Several groups have now independently detected full-length, intact, normal and mutant huntingtin in the nucleus. Here we discuss recent advances on studies of protein nuclear transport and how proteins enter the nucleus as well as cell biological studies of huntingtin protein. Recent data in publication suggest that wild-type huntingtin may have a normal nuclear role and that the nuclear transport dynamics of huntingtin may be affected during the course of HD. The potential roles of nuclear transport of huntingtin protein for normal biological function, and the consequences of potential nuclear transport defects in HD are discussed.