Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a < i > Drosophila < /i > model of Gaucher disease

by Magda L. Atilano, Alexander Hull, Catalina-Andreea Romila, Mirjam L. Adams, Jacob Wildfire, Enric Ure ña, Miranda Dyson, Jorge Ivan-Castillo-Quan, Linda Partridge, Kerri J. Kinghorn Mutations in theGBA1 gene cause the lysosomal storage disorder Gaucher disease (GD) and are the greatest known genetic risk factors for Parkinson ’s disease (PD). Communication between the gut and brain and immune dysregulation are increasingly being implicated in neurodegenerative disorders such as PD. Here, we show that flies lacking theGba1b gene, the main fly orthologue ofGBA1, display widespread NF-kB signalling activation, including gut inflammation, and brain glial activation. We also demonstrate intestinal autophagic defects, gut dysfunction, and microbiome dysbiosis. Remarkably, modulating the microbiome ofGba1b knockout flies, by raising them under germ-free conditions, partially ameliorates lifespan, locomotor and immune phenotypes. Moreover, we show that modulation of the immune deficiency (IMD) pathway is detrimental to the survival ofGba1 deficient flies. We also reveal that direct stimulation of autophagy by rapamycin treatment achieves similar benefits to germ-free conditions independent of gut bacterial load. Consistent with this, we show that pharmacologically blocking autophagosomal-lysosomal fusion, mimicking the autophagy defects ofGba1 depleted cells, is sufficient to stimulate intestinal immune activation. Overall, our data elucidate a mechanism whereby an altered mic...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research