Glycolysis inhibition decreases the levels of glutamate transporters and enhances glutamate neurotoxicity in the R6/2 Huntington's disease mice.
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.
Estrada-Sánchez
Ana María
AM
Departamento de Neuropatología Molecular, División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico DF, Mexico.
Montiel
Teresa
T
Massieu
Lourdes
L
D027322:Amino Acid Transport System X-AG / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism* / Q000633:toxicity; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000037:antagonists & inhibitors / Q000378:metabolism; D006019:Glycolysis; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism*; D007461:Iodoacetates / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic
D027322:Amino Acid Transport System X-AG; D007461:Iodoacetates; D018698:Glutamic Acid; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating)
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