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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Hutten, S; Usluer, S; Bourgeois, B; Simonetti, F; Odeh, HM; Fare, CM; Czuppa, M; Hruska-Plochan, M; Hofweber, M; Polymenidou, M; Shorter, J; Edbauer, D; Madl, T; Dormann, D.
Nuclear Import Receptors Directly Bind to Arginine-Rich Dipeptide Repeat Proteins and Suppress Their Pathological Interactions.
Cell Rep. 2020; 33(12):108538-108538 Doi: 10.1016/j.celrep.2020.108538 [OPEN ACCESS]
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Co-Autor*innen der Med Uni Graz
Bourgeois Benjamin Michel Rene
Madl Tobias
Usluer Sinem

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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. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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