Nuclear relocation of normal huntingtin

In Huntington's Disease (HD), the huntingtin protein (Htt) includes an expa nded polyglutamine domain. Since mutant Htt concentrates in the nucleus of affected neurons, we have inquired whether normal Htt (Q(16-23)) is also ab le to access the nucleus. We observe that a major pool of normal full-lengt h Htt of HeLa cells is anchored to endosomes and also detect RNase-sensitiv e nuclear foci which include a 70-kDa N-terminal Htt fragment. Agents which damage DNA trigger caspase-3-dependent cleavage of Htt and dramatically re locate the 70 kDa fragment to the nucleoplasm. Considering that polyglutami ne tracts stimulate caspase activation, mutant Htt is therefore poised to e nter the nucleus. These considerations help rationalize the nuclear accumul ation of Htt which is characteristic of HD and provide a first example of i nvolvement of caspase cleavage in release of membrane-bound proteins which subsequently enter the nucleus.