Glutamate is an excitatory neurotransmitter essential for function of the nervous system. Certain injurious conditions cause excess glutamate to accumulate at the synapse, resulting in hyperstimulation of the post-synaptic neuron that can cause cell death. Glutamate transporters play an essential role in neuronal health and function by removing excess glutamate from the synaptic cleft. Considerable evidence implicates defective glutamate transport in ALS. It is particularly striking that approximately 65% of sporadic ALS patients have been reported to express aberrant glutamate transporter transcripts in affected neurons, a phenotype correlated with inhibition of glutamate transport. We propose to conduct a thorough analysis of glutamate transporter mutations in the facile C. elegans model system. The genome of this animal (sequenced to completion) encodes six glutamate transporter genes. We will determine when, and in which cells, the transporters are expressed, we will characterize their biochemical properties, and we will determine the loss of function phenotypes of each. We will also analyze the effects of expressing aberrant transporter transcripts, analogous to some produced in ALS patients, in transgenic animals. Finally, we will exploit the full power of C. elegans genetic analysis to conduct screens for new mutations that reverse or modify transporter defects. Genes identified in these screens should advance understanding of both normal and aberrant glutamate signaling. Since the C. elegans model system offers several unique advantages and most biological processes are conserved, we expect that results of the proposed study should provide new insight into basic mechanisms of Glu regulation at the synapse and may suggest novel strategies for preventing neurodegeneration in ALS.
| Mano, Itzhak; Straud, Sarah; Driscoll, Monica (2007) Caenorhabditis elegans glutamate transporters influence synaptic function and behavior at sites distant from the synapse. J Biol Chem 282:34412-9 |
