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Nat Commun. 2019 Sep 13;10(1):4162. doi: 10.1038/s41467-019-12101-z.

The mutational landscape of a prion-like domain.

Author information

1
Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003, Barcelona, Spain. bbolognesi@ibecbarcelona.eu.
2
Institute of Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain. bbolognesi@ibecbarcelona.eu.
3
Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003, Barcelona, Spain.
4
Institute of Bioengineering of Catalonia (IBEC), The Barcelona Institute of Science and Technology, Barcelona, Spain.
5
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
6
Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010, Barcelona, Spain.
7
Department of Biology 'Charles Darwin', Sapienza University of Rome, P.le A. Moro 5, Rome, 00185, Italy.
8
Center for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Doctor Aiguader 88, 08003, Barcelona, Spain. ben.lehner@crg.eu.
9
Universitat Pompeu Fabra (UPF), Barcelona, Spain. ben.lehner@crg.eu.
10
Institució Catalana de Recerca i Estudis Avançats (ICREA), Passeig Lluís Companys 23, 08010, Barcelona, Spain. ben.lehner@crg.eu.

Abstract

Insoluble protein aggregates are the hallmarks of many neurodegenerative diseases. For example, aggregates of TDP-43 occur in nearly all cases of amyotrophic lateral sclerosis (ALS). However, whether aggregates cause cellular toxicity is still not clear, even in simpler cellular systems. We reasoned that deep mutagenesis might be a powerful approach to disentangle the relationship between aggregation and toxicity. We generated >50,000 mutations in the prion-like domain (PRD) of TDP-43 and quantified their toxicity in yeast cells. Surprisingly, mutations that increase hydrophobicity and aggregation strongly decrease toxicity. In contrast, toxic variants promote the formation of dynamic liquid-like condensates. Mutations have their strongest effects in a hotspot that genetic interactions reveal to be structured in vivo, illustrating how mutagenesis can probe the in vivo structures of unstructured proteins. Our results show that aggregation of TDP-43 is not harmful but protects cells, most likely by titrating the protein away from a toxic liquid-like phase.

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