Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization

Huntington disease (HD) is a genetically dominant condition caused by expan ded CAG repeats coding for glutamine in the HD gene product huntingtin(1). Although HD symptoms reflect preferential neuronal death in specific brain regions, huntingtin is expressed in almost all tissues(2), so abnormalities outside the brain might be expected. Although involvement of nuclei(3-7) a nd mitochondria(8-14) in HD pathophysiology has been suggested, specific in tracellular defects that might elicit cell death have been unclear. Mitocho ndria dysfunction is reported in HD brains(10-13); mitochondria are organel les that regulates apoptotic cell death(15,16). We now report that lymphobl asts derived from HD patients showed increased stress-induced apoptotic cel l death associated with caspase-3 activation. When subjected to stress, HD lymphoblasts also manifested a considerable increase in mitochondrial depol arization correlated with increased glutamine repeats.