Brain glyceraldehyde-3-phosphate dehydrogenase activity in human trinucleotide repeat disorders.
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.


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%).


CONCLUSIONS
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.
Kish
S J
SJ
Human Neurochemical Pathology Laboratory, Center for Addiction and Mental Health, Toronto, Ontario, Canada. kishs@cs.clarke-inst.on.ca
Lopes-Cendes
I
I
Guttman
M
M
Furukawa
Y
Y
Pandolfo
M
M
Rouleau
G A
GA
Ross
B M
BM
Nance
M
M
Schut
L
L
Ang
L
L
DiStefano
L
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000201:enzymology* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D005260:Female; D005986:Glyceraldehyde 3-Phosphate / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000235:genetics*; D010088:Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D017354:Point Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D018911:Trinucleotide Repeats / Q000235:genetics*
D005986:Glyceraldehyde 3-Phosphate; D010088:Oxidoreductases