Glutamate uptake is reduced in prefrontal cortex in Huntington's disease.
Huntington's disease (HD) is caused by a CAG repeat expansion in the HD gene, but how this mutation causes neuronal dysfunction and degeneration is unclear. Inhibition of glutamate uptake, which could cause excessive stimulation of glutamate receptors, has been found in animals carrying very long CAG repeats in the HD gene. In seven HD patients with moderate CAG expansions (40-52), repeat expansion and HD grade at autopsy were strongly correlated (r=0.88, p=0.0002). Uptake of [(3)H]glutamate was reduced by 43% in prefrontal cortex, but the level of synaptic (synaptophysin, AMPA receptors) and astrocytic markers (GFAP, glutamate transporter EAAT1) were unchanged. Glutamate uptake correlated inversely with CAG repeat expansion (r= -0.82, p=0.015). The reducing agent dithiothreitol improved glutamate uptake in controls, but not in HD brains, suggesting irreversible oxidation of glutamate transporters in HD. We conclude that impairment of glutamate uptake may contribute to neuronal dysfunction and degeneration in HD.
Hassel
Bjørnar
B
Norwegian Defense Research Establishment, P.O. Box 25, 2027 Kjeller, Norway. bjornar.hassel@ffi.no
Tessler
Shoshi
S
Faull
Richard L M
RL
Emson
Piers C
PC
D001253:Astrocytes / Q000473:pathology; D001692:Biological Transport; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D006816:Huntington Disease / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000473:pathology; D018911:Trinucleotide Repeats
D018698:Glutamic Acid