BRAIN GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE-ACTIVITY IN HUMAN TRINUCLEOTIDE REPEAT DISORDERS

Background: Although the abnormal gene products responsible for severa l hereditary neurodegenerative disorders caused by repeat CAG trinucle otides have been identified, the mechanism by which the proteins conta ining the expanded polyglutamine domains cause cell death is unknown. The observation that several of the mutant proteins interact in vitro with the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenas e (GAPDH) suggests that interaction between the different gene product s and GAPDH might damage brain neurons. Objective: To measure the acti vity of GAPDH in postmortem brain of patients with CAG repeat disorder s. Patients and Methods: Activity of GAPDH was measured in morphologic ally affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SC A1], SCA2, and SCA3-Machado-Joseph disease), in brains of patients wit h Friedreich ataxia (a GAA repeat disorder) and Alzheimer disease, and in brains of matched control subjects. Results: Brain GAPDH activity was normal in all groups with the exception of a slight but statistica lly significant region-specific reduction in the patients with Hunting ton disease (caudate nucleus, -12%) and Alzheimer disease (temporal co rtex, -19%). Conclusion: The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreve rsible inactivation or in increased activity of GAPDH in human brain.