Autophagic dysfunction and gut microbiota dysbiosis cause chronic immune activation in a Drosophila model of Gaucher disease.

Mutations in the GBA1 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 the Gba1b gene, the main fly orthologue of GBA1, 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 of Gba1b 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 of Gba1 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 of Gba1 depleted cells, is sufficient to stimulate intestinal immune activation. Overall, our data elucidate a mechanism whereby an altered microbiome, coupled with defects in autophagy, drive chronic activation of NF-kB signaling in a Gba1 loss-of-function model. It also highlights that elimination of the microbiota or stimulation of autophagy to remove immune mediators, rather than prolonged immunosuppression, may represent effective therapeutic avenues for GBA1-associated disorders.

Genome size and ploidy influence angiosperm species' biomass under nitrogen and phosphorus limitation.

Angiosperm genome sizes (GS) range c. 2400-fold, and as nucleic acids are amongst the most phosphorus- (P) and nitrogen (N)-demanding cellular biomolecules, we test the hypothesis that a key influence on plant biomass and species composition is the interaction between N and P availability and plant GS. We analysed the impact of different nutrient regimes on above-ground biomass of angiosperm species with different GS, ploidy level and Grime's C-S-R (competitive, stress-tolerant, ruderal) plant strategies growing at the Park Grass Experiment (Rothamsted, UK), established in 1856. The biomass-weighted mean GS of species growing on plots with the addition of both N and P fertilizer were significantly higher than that of plants growing on control plots and plots with either N or P. The plants on these N + P plots are dominated by polyploids with large GS and a competitive plant strategy. The results are consistent with our hypothesis that large genomes are costly to build and maintain under N and P limitation. Hence GS and ploidy are significant traits affecting biomass growth under different nutrient regimes, influencing plant community composition and ecosystem dynamics. We propose that GS is a critical factor needed in models that bridge the knowledge gap between biodiversity and ecosystem functioning.