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  • Nuclear Import Receptors Directly Bind to Arginine-Rich Dipeptide Repeat Proteins and Suppress Their Pathological Interactions.

Nuclear Import Receptors Directly Bind to Arginine-Rich Dipeptide Repeat Proteins and Suppress Their Pathological Interactions.

Cell reports (2020-12-29)
Saskia Hutten, Sinem Usluer, Benjamin Bourgeois, Francesca Simonetti, Hana M Odeh, Charlotte M Fare, Mareike Czuppa, Marian Hruska-Plochan, Mario Hofweber, Magdalini Polymenidou, James Shorter, Dieter Edbauer, Tobias Madl, Dorothee Dormann
ABSTRACT

Nuclear import receptors, also called importins, mediate nuclear import of proteins and chaperone aggregation-prone cargoes (e.g., neurodegeneration-linked RNA-binding proteins [RBPs]) in the cytoplasm. Importins were identified as modulators of cellular toxicity elicited by arginine-rich dipeptide repeat proteins (DPRs), an aberrant protein species found in C9orf72-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Mechanistically, the link between importins and arginine-rich DPRs remains unclear. Here, we show that arginine-rich DPRs (poly-GR and poly-PR) bind directly to multiple importins and, in excess, promote their insolubility and condensation. In cells, poly-GR impairs Impα/β-mediated nuclear import, including import of TDP-43, an RBP that aggregates in C9orf72-ALS/FTD patients. Arginine-rich DPRs promote phase separation and insolubility of TDP-43 in vitro and in cells, and this pathological interaction is suppressed by elevating importin concentrations. Our findings suggest that importins can decrease toxicity of arginine-rich DPRs by suppressing their pathological interactions.

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Sigma-Aldrich
Anti-Transportin 1 antibody, Mouse monoclonal, clone D45, purified from hybridoma cell culture
Supelco
SYPRO® Ruby Protein Gel Stain