title: Loss of SIRT4 decreases GLT-1-dependent glutamate uptake and increases sensitivity to kainic acid.
abstract: Glutamate transport is a critical process in the brain that maintains low extracellular levels of glutamate to allow for efficient neurotransmission and prevent excitotoxicity. Loss of glutamate transport function is implicated in epilepsy, traumatic brain injury, and amyotrophic lateral sclerosis. It remains unclear whether or not glutamate transport can be modulated in these disease conditions to improve outcome. Here, we show that sirtuin (SIRT)4, a mitochondrial sirtuin, is up-regulated in response to treatment with the potent excitotoxin kainic acid. Loss of SIRT4 leads to a more severe reaction to kainic acid and decreased glutamate transporter expression and function in the brain. Together, these results indicate a critical and novel stress response role for SIRT4 in promoting proper glutamate transport capacity and protecting against excitotoxicity.
authors.affiliation: Department of Neuroscience, Tufts University School of Medicine, Boston, Massachusetts, USA; Neuroscience Program, Tufts University Sackler School of Biomedical Sciences, Boston, Massachusetts, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Shih
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Andrew
authors.initials: A
authors.lastname: Mason
authors.forename: Haruki
authors.initials: H
authors.lastname: Higashimori
authors.forename: Gizem
authors.initials: G
authors.lastname: Donmez
mesh_terms: D000818:Animals; D019921:Biotinylation; D001921:Brain / Q000166:cytology / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D027342:Excitatory Amino Acid Transporter 2 / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism*; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000172:deficiency*; D009474:Neurons / Q000187:drug effects / Q000648:ultrastructure; D012640:Seizures / Q000139:chemically induced / Q000473:pathology; D037761:Sirtuins / Q000172:deficiency*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D027342:Excitatory Amino Acid Transporter 2; D024101:Mitochondrial Proteins; D018698:Glutamic Acid; C514813:SIRT4 protein, mouse; D037761:Sirtuins; D007608:Kainic Acid
keywords: GLT-1; excitotoxicity; glutamate transport; kainic acid; sirtuins