TDP-43 pathology in < i > Drosophila < /i > induces glial-cell type specific toxicity that can be ameliorated by knock-down of SF2/SRSF1

We report that TDP-43 pathology inDrosophila is sufficient to cause progressive loss of each of the 5 glial sub-types. But the effects on organismal survival were most pronounced when TDP-43 pathology was induced in the perineural glia (PNG) or astrocytes. In the case of PNG, this effect is not attributable to loss of the glial population, because ablation of these glia by expression of pro-apoptotic reaper expression has relatively little impact on survival. To uncover underlying mechanisms, we used cell-type-specific nuclear RNA sequencing to characterize the transcriptional changes induced by pathological TDP-43 expression. We identified numerous glial cell-type specific transcriptional changes. Notably, SF2/SRSF1 levels were found to be decreased in both PNG and in astrocytes. We found that further knockdown ofSF2/SRSF1 in either PNG or astrocytes lessens the detrimental effects of TDP-43 pathology on lifespan, but extends survival of the glial cells. Thus TDP-43 pathology in astrocytes or PNG causes systemic effects that shorten lifespan andSF2/SRSF1 knockdown rescues the loss of these glia, and also reduces their systemic toxicity to the organism.
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research