TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma\/Translocated in Sarcoma (FUS) are ribonucleoproteins associated with pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under physiological conditions, TDP-43 and FUS are predominantly localized in the nucleus, where they participate in transcriptional regulation, RNA splicing and metabolism. In disease, however, they are typically mislocalized to the cytoplasm where they form aggregated inclusions. A number of shared cellular pathways have been identified that contribute to TDP-43 and FUS toxicity in neurodegeneration. In the present study, we report a novel pathogenic mechanism shared by these two proteins. We found that pathological FUS co-aggregates with a ribosomal protein, the Receptor for Activated C-Kinase 1 (RACK1), in the cytoplasm of spinal cord motor neurons of ALS, as previously reported for pathological TDP-43. In HEK293T cells transiently transfected with TDP-43 or FUS mutant lacking a functional nuclear localization signal (NLS; TDP-43\u0394NLS<\/sup>\u00a0and FUS\u0394NLS<\/sup>), cytoplasmic TDP-43 and FUS induced co-aggregation with endogenous RACK1. These co-aggregates sequestered the translational machinery through interaction with the polyribosome, accompanied by a significant reduction of global protein translation. RACK1 knockdown decreased cytoplasmic aggregation of TDP-43\u0394NLS<\/sup>\u00a0or FUS\u0394NLS<\/sup>\u00a0and alleviated associated global translational suppression. Surprisingly, RACK1 knockdown also led to partial nuclear localization of TDP-43\u0394NLS<\/sup>\u00a0and FUS\u0394NLS<\/sup>\u00a0in some transfected cells, despite the absence of NLS. In vivo, RACK1 knockdown alleviated retinal neuronal degeneration in transgenic Drosophila melanogaster expressing hTDP-43WT<\/sup>\u00a0or hTDP-43Q331K<\/sup>\u00a0and improved motor function of hTDP-43WT<\/sup>\u00a0flies, with no observed adverse effects on neuronal health in control knockdown flies. In conclusion, our results revealed a novel shared mechanism of pathogenesis for misfolded aggregates of TDP-43 and FUS mediated by interference with protein translation in a RACK1-dependent manner. We provide proof-of-concept evidence for targeting RACK1 as a potential therapeutic approach for TDP-43 or FUS proteinopathy associated with ALS and FTLD.<\/p>\n","protected":false},"author":14,"featured_media":0,"template":"","meta":{"_acf_changed":false},"studies-relation":[],"class_list":["post-12471","ccna_publication","type-ccna_publication","status-publish","hentry"],"acf":[],"yoast_head":"\n