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RNA-binding proteins (RBPs) are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), but the underlying disease mechanisms remain unclear. In an unbiased screen in  Drosophila  for RBPs that genetically interact with TDP-43, we found that downregulation of the mRNA export factor  Ref1  (fly orthologue to human  ALYREF ) mitigated TDP-43 induced toxicity. Further,  Ref1  depletion also reduced toxicity caused by expression of the  C9orf72  GGGGCC repeat expansion.  Ref1  knockdown lowered the mRNA levels for these related disease genes and reduced the encoded proteins with no effect on a wild-type Tau disease transgene or a control transgene. Interestingly, expression of TDP-43 or the GGGGCC repeat expansion increased endogenous  Ref1  mRNA levels in the fly brain. Further, the human orthologue ALYREF was upregulated by immunohistochemistry in ALS motor neurons, with the strongest upregulation occurring in ALS cases harboring the GGGGCC expansion in  C9orf72 . These data support  ALYREF  as a contributor to ALS/FTD and highlight its downregulation as a potential therapeutic target that may affect co-existing disease etiologies.   Electronic supplementary material  The online version of this article (10.1186/s40478-019-0710-x) contains supplementary material, which is available to authorized users.

Drosophila Ref1/ALYREF regulates transcription and toxicity associated with ALS/FTD disease etiologies