HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells

Haiyang Yu, Shan Lu, Kelsey Gasior, Digvijay Singh, Sonia Vazquez-Sanchez, Olga Tapia, Divek Toprani, Melinda S. Beccari, John R. Yates, Sandrine Da Cruz, Jay M. Newby, Miguel Lafarga, Amy S. Gladfelter, Elizabeth Villa, Don W. Cleveland

Research output: Contribution to journalArticlepeer-review

74 Scopus citations

Abstract

The RNA binding protein TDP-43 forms intranuclear or cytoplasmic aggregates in age-related neurodegenerative diseases. In this study, we found that RNA binding-deficient TDP-43 (produced by neurodegeneration-causing mutations or posttranslational acetylation in its RNA recognition motifs) drove TDP-43 demixing into intranuclear liquid spherical shells with liquid cores. These droplets, which we named "anisosomes", have shells that exhibit birefringence, thus indicating liquid crystal formation. Guided by mathematical modeling, we identified the primary components of the liquid core to be HSP70 family chaperones, whose adenosine triphosphate (ATP)-dependent activity maintained the liquidity of shells and cores. In vivo proteasome inhibition within neurons, to mimic aging-related reduction of proteasome activity, induced TDP-43-containing anisosomes. These structures converted to aggregates when ATP levels were reduced. Thus, acetylation, HSP70, and proteasome activities regulate TDP-43 phase separation and conversion into a gel or solid phase.

Original languageEnglish (US)
Article numbereabb4309
JournalScience
Volume371
Issue number6529
DOIs
StatePublished - Feb 5 2021
Externally publishedYes

ASJC Scopus subject areas

  • General

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