MassIVE MSV000098098

Complete Public PXD068255

TDP-43 skein-like inclusions formed by BAG3/HSP70 guided co-aggregation with actin binding proteins attached to actin filaments

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Description

In multiple neurodegenerative diseases, the RNA binding protein TDP-43 forms cytoplasmic aggregates of distinct morphologies, including skein-like, spherical, diffuse, and granular inclusions. While the N-terminal self-oligomerization domain (NTD) regulates TDP-43 de-mixing into cytoplasmic droplets, inhibition of NTD-mediated oligomerization is shown here to promote the formation of skein-like inclusions. Utilizing proximity labeling/mass spectrometry, cellular stresses are shown to induce TDP-43 association with actin-binding proteins that include filamins and beta actinin. Small interfering RNA-mediated reduction of filamin in Drosophila ameliorates cell loss from cytoplasmic TDP-43, consistent with filamin/TDP-43 interaction enhancing cytotoxicity. TDP-43s association with actin-binding proteins is mediated by BAG3, a HSP70 family nucleotide exchange factor (NEF) that regulates proteostasis of actin-binding proteins. BAG2, another HSP70 NEF facilitates the formation of small, rounded TDP-43 inclusions. Our evidence demonstrates that both TDP-43 self-oligomerization and its binding partners, including HSP70 and the co-chaperones BAG2 and BAG3, drive formation of different types of TDP-43 inclusions. [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: TDP43 ; DatasetType:Proteomics

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Principal Investigators:
(in alphabetical order) 		Don W. Cleveland, Ludwig Institute for Cancer Research, Department of Cellular and Molecular Medicine, Univ. of California, United States
Submitting User: jdiedrich
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