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

Nature communications (2017-07-21)
Ping Wang, Connor M Wander, Chao-Xing Yuan, Michael S Bereman, Todd J Cohen
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.TDP-43 aggregation is linked to various diseases including amyotrophic lateral sclerosis. Here the authors show that acetylation of the protein triggers TDP-43 pathology in cultured cells and mouse skeletal muscle, which can be cleared through an HSF1-dependent chaperone mechanism that disaggregates the protein.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Dulbecco′s Modified Eagle′s Medium - high glucose, With 4500 mg/L glucose, L-glutamine, and sodium bicarbonate, without sodium pyruvate, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Triton X-100, laboratory grade
Sigma-Aldrich
N-p-Tosyl-L-phenylalanine chloromethyl ketone, ≥97% (TLC), powder
Sigma-Aldrich
17-(Allylamino)-17-demethoxygeldanamycin, ≥98% (HPLC), solid
Sigma-Aldrich
Anti-phospho-TDP-43 (pSer410) antibody produced in rabbit, ~1.0 mg/mL, affinity isolated antibody
Sigma-Aldrich
MISSION® esiRNA, targeting human HSF1

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