Increased vesicular glutamate transporter expression causes excitotoxic neurodegeneration.
Increases in vesicular glutamate transporter (VGLUT) levels are observed after a variety of insults including hypoxic injury, stress, methamphetamine treatment, and in genetic seizure models. Such overexpression can cause an increase in the amount of glutamate released from each vesicle, but it is unknown whether this is sufficient to induce excitotoxic neurodegeneration. Here we show that overexpression of the Drosophila vesicular glutamate transporter (DVGLUT) leads to excess glutamate release, with some vesicles releasing several times the normal amount of glutamate. Increased DVGLUT expression also leads to an age-dependent loss of motor function and shortened lifespan, accompanied by a progressive neurodegeneration in the postsynaptic targets of the DVGLUT-overexpressing neurons. The early onset lethality, behavioral deficits, and neuronal pathology require overexpression of a functional DVGLUT transgene. Thus overexpression of DVGLUT is sufficient to generate excitotoxic neuropathological phenotypes and therefore reducing VGLUT levels after nervous system injury or stress may mitigate further damage.
Daniels
Richard W
RW
Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Miller
Bradley R
BR
DiAntonio
Aaron
A
D000818:Animals; D030801:Animals, Genetically Modified; D016922:Cellular Senescence / Q000235:genetics; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D008136:Longevity / Q000235:genetics; D008297:Male; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009498:Neurotoxins / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D017729:Presynaptic Terminals / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics*; D050496:Vesicular Glutamate Transport Proteins / Q000096:biosynthesis* / Q000235:genetics
D009498:Neurotoxins; D050496:Vesicular Glutamate Transport Proteins