Overexpression of Dmel\VGlut leads to age-dependent loss of motor function and shortened lifespan; these phenotypes are characteristic of fly models of neurodegenerative disease. VGlut encodes one of a large family membrane transport proteins (solute carriers); it is most closely related to the SLC17A6, SLC17A7, and SLC17A8 genes in human, which mediate the uptake of glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells. SLC17A8 has been implicated in a form of autosomal deafness (MIM:605583). Classical loss-of-function alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated for Dmel\VGlut.
None of the human SLC17A genes has been introduced into flies.
Overexpression of the Dmel\VGlut in glutamatergic neurons leads to excess glutamate release, with some vesicles releasing several times the normal amount of glutamate. Age-dependent loss of motor function and shortened lifespan are observed, accompanied by a progressive neurodegeneration in the postsynaptic targets of the VGlut-overexpressing neurons. In the fly model, dopamine (DA) neurons appear to be highly sensitive to VGlut expression; the balance of VGlut expression within the dopaminergic system influences DA neuron survival and vulnerability to neurodegeneration.
Amorphic mutations of a microRNA believed to regulate the level of VGlut mRNAs also result in neurodegenerative phenotypes; see 'neurodegenerative disease (postulated), MIR137-related' (FBhh0000760).
Sex differences in age-related DA neurodegeneration and its associated locomotor behavior are observed in Drosophila; males exhibit significantly greater decreases in both DA neuron number and locomotion during aging compared with females. Dynamic changes in DA neuron VGlut expression appear to mediate these age- and sex-related differences. Female Drosophila exhibit higher levels of VGlut expression in DA neurons compared with males; this finding is conserved across flies, rodents, and humans.
[updated Jun. 2021 by FlyBase; FBrf0222196]
SLC17A6, SLC17A7, and SLC17A8 encode vesicle-bound, sodium-dependent phosphate transporters that are specifically expressed in the neuron-rich regions of the brain. Associated preferentially with the membranes of synaptic vesicles, they mediate the uptake of glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells. [Gene Cards, SLC17A6, SLC17A7, SLC17A8; 2018.07.20]
Many to many: large gene family in both species. SLC17A8 is most closely related to Dmel\VGlut.
Many to many: large gene family in both species. SLC17A6 is most closely related to Dmel\VGlut.
Many to many: large gene family in both species. SLC17A7 is most closely related to Dmel\VGlut.
High-scoring ortholog of human SLC17A6, SLC17A7, and SLC17A8 (many to many; closest orthologs: 1 Drosophila to 3 human). DmelVGlut shares 44-47% identity and 58-61% similarity with the human genes.
