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

Ping Wang,Michael S Bereman,Todd J Cohen,Connor M Wander,Chao-Xing Yuan

doi:10.1038/s41467-017-00088-4

Ping Wang, Michael S Bereman + Show 3 more

Open Access

https://doi.org/10.1038/s41467-017-00088-4

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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.

Highlights

TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis
We hypothesized that TDP-43 aggregation would be conserved in both skeletal muscle and central nervous system (CNS) tissues, both of which are vulnerable to TDP-43 pathology
A single acetylation-mimic (K145Q) that modulates TDP-43 RNA regulatory functions led to robust aggregation that was sufficient, when targeted to the cytoplasm, to trigger many of the pathological hallmarks associated with TDP-43 proteinopathy including hyper-phosphorylation, recruitment of functionally linked amyotrophic lateral sclerosis (ALS) proteins, perturbations of mitochondria, and an associated inflammatory signature

Summary

Introduction

TDP-43 pathology marks a spectrum of multisystem proteinopathies including amyotrophic lateral sclerosis, frontotemporal lobar degeneration, and sporadic inclusion body myositis. In addition to the central nervous system (CNS), TDP-43 forms pathological inclusions in skeletal muscles of patients with sporadic inclusion body myositis (sIBM)[12,13,14,15,16], suggesting TDP-43 pathology is not solely limited to vulnerable neurons, but likely induces multisystem proteinopathy in susceptible cell types It is not fully understood how TDP-43 causes cellular toxicity, substantial evidence indicates that TDP-43 aggregates induce loss of normal nuclear TDP-43 functions, as nuclear depletion of normally soluble TDP-43 and sequestration into inclusions leads to reduced splicing and RNA stability as well as activation of cryptic splice sites in cultured cells and transgenic a Intensity (%) TGHSkGFGFVR 100 y4. As a compensatory response to loss of TDP-43 function, auto-regulation of the TARDBP transcript increases TDP-43 levels[20,21,22], thereby generating a feed-forward pathogenic cycle consisting of sustained accumulation of cytosolic TDP-43 that further compromises normal nuclear TDP-43 functions and potentially alters expression of ~6000 target genes, as shown by genome-wide TDP-43-binding studies[19, 23, 24]

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