Acetylation-induced TDP-43 pathology is suppressed by an HSF1-dependent chaperone program

Ping Wang, Connor M. Wander, Chao-Xing Yuan, Michael S. Bereman and Todd J. Cohen ()
Additional contact information
Ping Wang: University of North Carolina
Connor M. Wander: University of North Carolina
Chao-Xing Yuan: Alexion Pharmaceuticals Inc
Michael S. Bereman: North Carolina State University
Todd J. Cohen: University of North Carolina

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. Surprisingly, it has been challenging to recapitulate this pathology, highlighting an incomplete understanding of TDP-43 regulatory mechanisms. Here we provide evidence supporting TDP-43 acetylation as a trigger for disease pathology. Using cultured cells and mouse skeletal muscle, we show that TDP-43 acetylation-mimics promote TDP-43 phosphorylation and ubiquitination, perturb mitochondria, and initiate degenerative inflammatory responses that resemble sporadic inclusion body myositis pathology. Analysis of functionally linked amyotrophic lateral sclerosis proteins revealed recruitment of p62, ubiquilin-2, and optineurin to TDP-43 aggregates. We demonstrate that TDP-43 acetylation-mimic pathology is potently suppressed by an HSF1-dependent mechanism that disaggregates TDP-43. Our study illustrates bidirectional TDP-43 processing in which TDP-43 aggregation is targeted by a coordinated chaperone response. Thus, activation or restoration of refolding mechanisms may alleviate TDP-43 aggregation in tissues that are uniquely susceptible to TDP-43 proteinopathies.

Date: 2017
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41467-017-00088-4 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00088-4

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-017-00088-4

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().