Glutamine synthetase-1 ameliorates neuronal degeneration in a Drosophila model of Huntington's Disease by promoting autophagy

Huntington’s Disease (HD) is an inherited disease caused by the expansion of a CAG trinucleotide, which results in translation of a protein containing an enlarged polyglutamine (polyQ) domain. HD is characterized by the progressive degeneration of neurons, resulting in involuntary movement, dementia and death. Neuronal cell death is caused by an excess of glutamate, that is maintained at physiological level by a non autonomous cycle between glia and neurons, also called the glutamate-glutamine cycle. Taking advantage of a Drosophila model for HD we try to understand if modulation of components of the glutamate-glutamine cycle could have beneficial effects on neuronal degeneration induced by expression of the human mutant HttQ93 responsible for HD. By genetic and biochemical approaches, we demonstrated that the expression of the enzyme glutamine synthetase (GS1) in neurons ameliorates HD phenotypes by improving motor function in hHttQ93 animals. In addition we found that GS1 exerts its protective role by promoting autophagy through inhibition of TOR signaling pathway, a process that correlates with a reduced amount of hHttQ93 protein aggregates. We are now focusing our efforts to dissect more in details the relationship between glutamate- glutamine catabolism and the autophagic process in neuronal and glial cells, in normal and pathological conditions. Our data could be useful to provide new insights into the molecular mechanisms that protect neurons from death and so, to some extent, to find new potential therapeutic targets.