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Glycolysis Inhibition Decreases the Levels of Glutamate Transporters and Enhances Glutamate Neurotoxicity in the R6/2 Huntington′s Disease Mice

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Abstract

Excitotoxicity has been associated with the loss of medium spiny neurons (MSN) in Huntington’s disease (HD). We have previously observed that the content of the glial glutamate transporters, glutamate transporter 1 (GLT-1) and glutamate-aspartate transporter (GLAST), diminishes in R6/2 mice at 14 weeks of age but not at 10 weeks, and that this change correlates with an increased vulnerability of striatal neurons to glutamate toxicity. We have also reported that inhibition of the glycolytic pathway decreases glutamate uptake and enhances glutamate neurotoxicity in the rat brain. We now show that at 10-weeks of age, glutamate excitotoxicity is precipitated in R6/2 mice, after the treatment with iodoacetate (IOA), an inhibitor of the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH). IOA induces a larger inhibition of GAPDH in R6/2 mice, while it similarly reduces the levels of GLT-1 and GLAST in wild-type and transgenic animals. Results suggest that metabolic failure and altered glutamate uptake are involved in the vulnerability of striatal neurons to glutamate excitotoxicity in HD.

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Acknowledgments

The authors thank Mr. Héctor Malagón for his help in the care and handling of transgenic mice at the animal house. This work was supported by PAPITT (UNAM) IN213507 grant to LM and CONACyT 194940 fellowship to AM Estrada-Sánchez.

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  1. Departamento de Neuropatología Molecular, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, AP 70-253, Mexico DF, CP 04510, Mexico

    Ana María Estrada-Sánchez, Teresa Montiel & Lourdes Massieu

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  1. Ana María Estrada-Sánchez
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  2. Teresa Montiel
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  3. Lourdes Massieu
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Correspondence to Lourdes Massieu.

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Estrada-Sánchez, A.M., Montiel, T. & Massieu, L. Glycolysis Inhibition Decreases the Levels of Glutamate Transporters and Enhances Glutamate Neurotoxicity in the R6/2 Huntington′s Disease Mice. Neurochem Res 35, 1156–1163 (2010). https://doi.org/10.1007/s11064-010-0168-5

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