TY - JOUR
T1 - HSP70 chaperones RNA-free TDP-43 into anisotropic intranuclear liquid spherical shells
AU - Yu, Haiyang
AU - Lu, Shan
AU - Gasior, Kelsey
AU - Singh, Digvijay
AU - Vazquez-Sanchez, Sonia
AU - Tapia, Olga
AU - Toprani, Divek
AU - Beccari, Melinda S.
AU - Yates, John R.
AU - Da Cruz, Sandrine
AU - Newby, Jay M.
AU - Lafarga, Miguel
AU - Gladfelter, Amy S.
AU - Villa, Elizabeth
AU - Cleveland, Don W.
N1 - Funding Information:
We thank the following for funding support: D.W.C., NINDS R01-NS027036 and the NOMIS Foundation; H.Y., NIA F32-AG059358 and NINDS K99-NS114162; K.G., NSF DMS-1816630; D.S., Damon Runyon Foundation DRG- 2364-19; M.S.B., NIGMS T32-GM008666; J.R.Y., NIGMS P41- GM103533; J.M.N., the NSERC (RGPIN-2019-06435, RGPAS-2019- 00014, and DGECR-2019-00321) and NSF (DMS-171474 and DMS-1816630); S.D.C., NINDS R01-NS027036; M.L., CIBERNED, CB06/05/0037; A.S.G., NIGMS R01-GM081506; E.V., The Pew Charitable Trust Scholars Program and NSF MRI DBI-1920374; and UCSD microscopy core, NINDS P30-NS047101. The UC San Diego cryo-EM facility is partially funded by a gift from the Agouron Institute.
Publisher Copyright:
© 2021 American Association for the Advancement of Science. All rights reserved.
PY - 2021/2/5
Y1 - 2021/2/5
N2 - 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.
AB - 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.
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U2 - 10.1126/science.abb4309
DO - 10.1126/science.abb4309
M3 - Article
C2 - 33335017
AN - SCOPUS:85099312683
VL - 371
JO - Science
JF - Science
SN - 0036-8075
IS - 6529
M1 - eabb4309
ER -