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Brain Glyceraldehyde-3-Phosphate Dehydrogenase Activity in Human Trinucleotide Repeat Disorders
Stephen J. Kish, PhD;
Iscia Lopes-Cendes, MD, PhD;
Mark Guttman, MD;
Yoshiaki Furukawa, MD;
Massimo Pandolfo, MD;
Guy A. Rouleau, MD, PhD;
Brian M. Ross, PhD;
Martha Nance, MD;
Lawrence Schut, MD;
Lee Ang, MD;
Linda DiStefano, BSc
Arch Neurol. 1998;55:1299-1304.
Background Although the abnormal gene products responsible for several hereditary neurodegenerative disorders caused by repeat CAG trinucleotides have been identified, the mechanism by which the proteins containing 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 dehydrogenase (GAPDH) suggests that interaction between the different gene products and GAPDH might damage brain neurons.
Objective To measure the activity of GAPDH in postmortem brain of patients with CAG repeat disorders.
Patients and Methods Activity of GAPDH was measured in morphologically affected and unaffected brain areas of patients with 4 different CAG repeat disorders (Huntington disease, spinocerebellar ataxia 1 [SCA1], SCA2, and SCA3–Machado-Joseph disease), in brains of patients with 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 statistically significant region-specific reduction in the patients with Huntington disease (caudate nucleus, -12%) and Alzheimer disease (temporal cortex, -19%).
Conclusion The presence of the polyglutamine-containing proteins in CAG repeat disorders does not result in substantial irreversible inactivation or in increased activity of GAPDH in human brain.
From the Human Neurochemical Pathology Laboratory, Center for Addiction and Mental Health, Toronto, Ontario (Drs Kish, Guttman, Furukawa, and Ross and Ms DiStefano); Departamento de Genética Médica, Universidade Estadual de Campinas, Campinas, Brazil (Dr Lopes-Cendes); Centre de Recherche Louis-Charles Simard (Dr Pandolfo) and Montreal General Hospital Research Institute (Dr Rouleau), Montreal, Quebec; the Department of Neurology, University of Minnesota, Minneapolis (Drs Nance and Schut); and the Department of Pathology, Sunnybrook Hospital, Toronto (Dr Ang).
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