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

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.

Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria

 Fuente: Science 05 Feb 2021, Vol. 371, Issue 6529, eabb4309

Editorial: American Association for the Advancement of Science

 Fecha de publicación: 01/05/2021

Nº de páginas: 15

Tipo de publicación: Artículo de Revista

 DOI: 10.1126/science.abb4309

ISSN: 0036-8075,1095-9203

Autores/as

YU, HAIYANG

LU, SHAN

GASIOR, KELSEY

SINGH, DIGVIJAY

VAZQUEZ SÁNCHEZ, SONIA

OLGA TAPIA MARTINEZ

TOPRANI, DIVEK

BECCARI, MELINDA S

YATES III, JOHN R

DA CRUZ, SANDRINE

NEWBY, JAY M

MIGUEL ANGEL LAFARGA COSCOJUELA

GLADFELTER, AMY S

VILLA, ELIZABETH

CLEVELAND, DON W