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

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-...

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Published in:	Science (American Association for the Advancement of Science) Vol. 371; no. 6529
Main Authors:	Yu, Haiyang, Lu, Shan, Gasior, Kelsey, Singh, Digvijay, Vazquez-Sanchez, Sonia, Tapia, Olga, Toprani, Divek, Beccari, Melinda S, Yates, 3rd, John R, Da Cruz, Sandrine, Newby, Jay M, Lafarga, Miguel, Gladfelter, Amy S, Villa, Elizabeth, Cleveland, Don W
Format:	Journal Article
Language:	English
Published:	United States The American Association for the Advancement of Science 05-02-2021
Subjects:	Adenosine triphosphate Aggregates Aging Aging - metabolism Amyotrophic lateral sclerosis Anatomy Animals Anisotropy ATP Chaperones Cores Cryoelectron Microscopy Dementia disorders Deoxyribonucleic acid DNA DNA-Binding Proteins - chemistry DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Gels HEK293 Cells Histone Deacetylases - metabolism HSP70 Heat-Shock Proteins - metabolism Hsp70 protein Humans Inhibition Liquid Crystals - chemistry Liquidity Mathematical Models Mice Mice, Inbred C57BL Mutation Neurodegeneration Neurodegenerative Diseases - genetics Neurodegenerative Diseases - metabolism Neurons - metabolism Proteasome Endopeptidase Complex - metabolism Proteasome Inhibitors - pharmacology Proteasomes Protein Aggregates Protein Domains Rats Rats, Sprague-Dawley Ribonucleic acid RNA RNA-Binding Proteins - genetics RNA-Binding Proteins - metabolism Rodents Spherical shells
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Florida State University Department of Mathematics, 1017 Academic Way, Tallahassee, FL 32306. Author contributions: H.Y., S.L., S.V.S. and D.W.C. designed most of the experiments. H.Y., S.L., S.V.S. performed most of the experiments. K.G., J.N. and A.S.G. designed and performed the mathematical modeling. D.S. and E.V. designed and performed the Cryo-ET. O.T. and M.L. designed and performed the EM and immunoEM in rat DRG neurons. D.T. helped in generating key materials. J.R.Y. supervised the proteomic experiments and analyses. H.Y., K.G. and D.W.C. wrote the original draft. A.S.G., E.V., N.J., M.L., S.D.C. and S.V.S. reviewed and edited the manuscript.
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.abb4309