Decreasing Glutamate Buffering Capacity Triggers Oxidative Stress and Neuropil Degeneration in the Drosophila Brain

Abstract

L-glutamate is both the major brain excitatory neurotransmitter and a potent neurotoxin in mammals. Glutamate excitotoxicity is partly responsible for cerebral traumas evoked by ischemia and has been implicated in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). In contrast, very little is known about the function or potential toxicity of glutamate in the insect brain. Here, we show that decreasing glutamate buffering capacity is neurotoxic in Drosophila. We found that the only Drosophila high-affinity glutamate transporter, dEAAT1, is selectively addressed to glial extensions that project ubiquitously through the neuropil close to synaptic areas. Inactivation of dEAAT1 by RNA interference led to characteristic behavior deficits that were significantly rescued by expression of the human glutamate transporter hEAAT2 or the administration in food of riluzole, an anti-excitotoxic agent used in the clinic for human ALS patients. Signs of oxidative stress included hypersensitivity to the free radical generator paraquat and rescue by the antioxidant melatonin. Inactivation of dEAAT1 also resulted in shortened lifespan and marked brain neuropil degeneration characterized by widespread microvacuolization and swollen mitochondria. This suggests that the dEAAT1-deficient fly provides a powerful genetic model system for molecular analysis of glutamate-mediated neurodegeneration.

A novel Omega-class glutathione S-transferase gene in Apis cerana cerana: molecular characterisation of GSTO2 and its protective effects in oxidative stress

“…After an overnight exposure, the killing zones around the drug-soaked filters were measured A tissue-specific expression analysis revealed that AccGSTO2 mRNA was expressed at its highest levels in the brain (Fig. 4b), which is very sensitive to oxidative stress (Ament et al 2008;Rival et al 2004). This observation is inconsistent with the low expression of GSTO in the mammalian brain (Board et al 2000).…”

Cellular senescence in honey bee brain is largely independent of chronological age

“…The brain was chosen for examination because it is sensitive to highly reactive oxygen (hROS) and nitrogen species (hRNS) (Bowling and Beal, 1995;Tyurin et al, 2000;Rival et al, 2004). If not counteracted by free radical defense mechanisms, reactive oxygen (ROS) and nitrogen species (RNS) cause damage to cellular components via protein oxidation and nitration (Sohal and Weindruch, 1996;Sohal, 2002).…”

Les astrocytes dans la chorée de Huntington

“…On notera que les mouches meurent aussi vite lorsque la protéine pathogène est exprimée dans les cellules gliales avec repo ou dans les neurones avec le promoteur du gène elav. Sur le plan cellulaire, la présence de la protéine Huntingtine mutée dans les cellules gliales réduit progressivement l'expression de EAAT1, l'unique transporteur de glutamate chez la drosophile [18], mais n'affecte pas significativement la survie de ces cellules [19]. Ces données apportent des arguments en faveur d'une action directe de la Huntingtine mutée sur le fonctionnement des astrocytes dans la chorée de Huntington.…”