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

• DOI: 10.1186/s40478-019-0710-x
• Publication Date: 2019-04-29T08:02:44Z
• Authors: Amit Berson; Lindsey D. Goodman; Ashley N. Sartoris; Charlton G. Otte; James A. Aykit; Virginia M.-Y. Lee; John Q. Trojanowski; Nancy M. Bonini
• Keywords: C9ORF72

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 TDP-43, we found downregulation of mRNA export factor Ref1 (fly orthologue to human ALYREF) mitigated TDP-43 induced toxicity. Further, depletion also reduced toxicity caused by expression C9orf72 GGGGCC repeat expansion. knockdown lowered levels these related genes encoded no effect on a wild-type Tau transgene or control transgene. Interestingly, expansion increased endogenous fly brain. ALYREF was upregulated immunohistochemistry ALS motor neurons, strongest upregulation occurring cases harboring C9orf72. These data support as contributor ALS/FTD highlight its potential therapeutic target may affect co-existing etiologies.