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Glutamate Uptake is Reduced in Prefrontal Cortex in Huntington’s Disease

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Abstract

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 [3H]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.

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Acknowledgments

The authors wish to thank Professor NC Danbolt for generously contributing antibodies to EAAT2 and for his valuable help in establishing the proteoliposome assay. The authors are grateful to Mrs EG Iversen for expert technical assistance. BH, ST, and PCE acknowledges the support of The Medical Research Council, UK, The Biotechnology and Biological Sciences Research Council, UK, RLMF acknowledges the support of The New Zealand Neurological Foundation.

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Correspondence to Bjørnar Hassel.

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Special issue article in honor of Dr. Frode Fonnum.

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Hassel, B., Tessler, S., Faull, R.L.M. et al. Glutamate Uptake is Reduced in Prefrontal Cortex in Huntington’s Disease. Neurochem Res 33, 232–237 (2008). https://doi.org/10.1007/s11064-007-9463-1

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