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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Bolognesi B,Faure AJ,Seuma M,Schmiedel JM,Tartaglia GG,Lehner Bdoi
10.1038/s41467-019-12101-zsubject
Has Abstractpub_date
2019-09-13 00:00:00pages
4162issue
1issn
2041-1723pii
10.1038/s41467-019-12101-zjournal_volume
10pub_type
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