Alteration of nuclear glyceraldehyde-3-phosphate dehydrogenase structure in Huntington's disease fibroblasts.

The expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) may be involved in neuronal disease and in programmed cell death. Recent investigations indicate an in vitro physical association between GAPDH and huntingtin, the mutated protein in Huntington's disease (HD). Previous studies reveal the functional diversity of GAPDH as a membrane, cytoplasmic and nuclear protein. These activities are independent of its classical glycolytic function. Thus, huntingtin-GAPDH interactions could affect not only energy production but also result in pleiotropic effects involving various biochemical pathways in HD cells. We now report the identification of a nuclear high molecular weight (HMW) GAPDH species in Huntington's disease cells. In contrast, nuclei from age-matched control normal human cells did not contain the HMW GAPDH species. Further, this GAPDH structure was not observed in HD whole cell sonicates which are characterized by normal GAPDH activity. The disruption of intracellular structure is implicit in the preparation of whole cell sonicates. Therefore, these results suggest that the dissociation of the GAPDH protein from its high molecular weight structure results in the recovery of its function. These findings reveal a singular, new subcellular phenotype in HD cells. As such, they indicate an interrelationship between nuclear GAPDH function and huntingtin localization in this CAG expansion neuronal disease.