Study on the mechanisms that induce autophagy in glia cells versus neurons in a Drosophila model for Huntington’s disease

Autophagy is a highly conserved homeostasis and quality control intracellular pathway widely linked to neurodegenerative and metabolic diseases, cancer and aging. Autophagy has been reported to protect from neurodegeneration in many polyQ disease models, such as HD, Parkinson or Spinocerebellar ataxia, and data suggest that loss of autophagy function is a central feature of neurodegenerative disease. In neurons autophagy is the major clearance process able to decrease cellular debris including the intracellular protein aggregates that are produced in human pathologies like Huntington disease (HD). HD is an inherited neurodegenerative disorder caused by the expansion of a CAG triplet in the first exon of the gene. This encodes for an abnormal mutant Huntingtin (Htt) protein that induces neuronal death. One of the most responsible cause of neuronal cell death is the excitotoxicity induced by an excess of glutamate: its level in the CNS is maintained constant thanks to Glutamine-Glutamate cycle established between neurons and glial cells. Our studies demonstrate that the modulation of the enzyme Glutamine-synthetase 1 (GS1) that converts glutamate in glutamine, in neurons ameliorates the phenotype of animals expressing HttQ93. In neurons GS1 is able to induce TOR-dependent autophagy, with the result of the degradation of mutated protein aggregates partially rescuing the disease phenotype. In the same manner we are also testing the relationship of GS1and autophagy in glial cells: our preliminary studies show that the inhibition of macroautophagy in glial cells expressing human HttQ93 is not limiting the rescue induced by GS1. This data suggest that in glial cells HD degeneration affects fly viability, through a different pathway than the one involved in brain neuronal toxicity. There are three major types of autophagy related to different pathway: chaperone-mediated autophagy (CMA), microautophagy (a direct engulfment of cytoplasmic components) and macroautophagy (which is TOR dependent). We’re currently investigating the role of autophagy in glial cells in the context of a HD disease, trying to understand if a different type of autophagy, a different pathway or different enzymes are involved and in which manner they contribute to the progression of neurodegeneration.