Yu H(1), Lu S(#)(2), Gasior K(#)(3)(4), Singh D(5), Vazquez-Sanchez S(2), Tapia O(6)(7), Toprani D(2), Beccari MS(2)(8), Yates JR 3rd(9), Da Cruz S(2)(10)(11), Newby JM(12), Lafarga M(6)(7)(13), Gladfelter AS(3)(14), Villa E(5), Cleveland DW(1)(8). Author information:
(1)Ludwig Institute for Cancer Research, University of California at San Diego,
La Jolla, CA, USA. [Email] [Email]
(2)Ludwig Institute for Cancer Research, University of California at San Diego,
La Jolla, CA, USA.
(3)Department of Biology, University of North Carolina at Chapel Hill, Chapel
Hill, NC, USA.
(4)Department of Mathematics, University of North Carolina at Chapel Hill,
Chapel Hill, NC, USA.
(5)Division of Biological Sciences, University of California, San Diego, San
Diego, CA, USA.
(6)Centro de Investigación Biomédica en Red sobre Enfermedades
Neurodegenerativas (CIBERNED), Madrid, Spain.
(7)Instituto de Investigación Sanitaria Valdecilla (IDIVAL), Santander, Spain.
(8)Department of Cellular and Molecular Medicine, University of California at
San Diego, La Jolla, CA, USA.
(9)Departments of Molecular Medicine and Neurobiology, The Scripps Research
Institute, La Jolla, CA, USA.
(10)VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
(11)Department of Neurosciences, KU Leuven, Leuven, Belgium.
(12)Department of Mathematical and Statistical Sciences, University of Alberta,
Edmonton, Alberta, Canada.
(13)Department of Anatomy and Cell Biology, University of Cantabria, Santander,
(14)Marine Biological Laboratory, Woods Hole, MA, USA.
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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