Functional and dynamic polymerization of the ALS-linked protein TDP-43 antagonizes its pathologic aggregation

Tariq Afroz,Patrick Ernst,Chiara Foglieni,Frédéric H T Allain,Melanie Jambeau,Andreas Plückthun,Florent Laferriere,Peer Mittl,Larissa A B Gilhespy,Zuzanna Maniecka,Paolo Paganetti,Magdalini Polymenidou,Eva-Maria Hock

doi:10.1038/s41467-017-00062-0

Tariq Afroz, Patrick Ernst + Show 11 more

Open Access

https://doi.org/10.1038/s41467-017-00062-0

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Abstract

TDP-43 is a primarily nuclear RNA-binding protein, whose abnormal phosphorylation and cytoplasmic aggregation characterizes affected neurons in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Here, we report that physiological nuclear TDP-43 in mouse and human brain forms homo-oligomers that are resistant to cellular stress. Physiological TDP-43 oligomerization is mediated by its N-terminal domain, which can adopt dynamic, solenoid-like structures, as revealed by a 2.1 Å crystal structure in combination with nuclear magnetic resonance spectroscopy and electron microscopy. These head-to-tail TDP-43 oligomers are unique among known RNA-binding proteins and represent the functional form of the protein in vivo, since their destabilization results in loss of alternative splicing regulation of known neuronal RNA targets. Our findings indicate that N-terminal domain-driven oligomerization spatially separates the adjoining highly aggregation-prone, C-terminal low-complexity domains of consecutive TDP-43 monomers, thereby preventing low-complexity domain inter-molecular interactions and antagonizing the formation of pathologic aggregates.

Highlights

This page was generated automatically upon download from the ETH Zurich Research Collection
TDP-43 is a multifunctional and essential RNA-binding protein (RBP), whose abnormal cytoplasmic misaccumulation is integrally linked to the pathogenesis of Amyotrophic lateral sclerosis (ALS) and FTD1, 2
We provide evidence that the physiological TDP-43 state in the nucleus is oligomeric and that this oligomerization is indispensable for the functional role of the protein in RNA metabolism

Summary

Introduction

This page was generated automatically upon download from the ETH Zurich Research Collection. TDP-43 is a primarily nuclear RNA-binding protein, whose abnormal phosphorylation and cytoplasmic aggregation characterizes affected neurons in patients with amyotrophic lateral sclerosis and frontotemporal dementia. Physiological TDP-43 oligomerization is mediated by its N-terminal domain, which can adopt dynamic, solenoid-like structures, as revealed by a 2.1 Å crystal structure in combination with nuclear magnetic resonance spectroscopy and electron microscopy. These head-to-tail TDP-43 oligomers are unique among known RNA-binding proteins and represent the functional form of the protein in vivo, since their destabilization results in loss of alternative splicing regulation of known neuronal RNA targets. A small fraction of TDP-43 was reported to exist as dimers in cells, which led to speculation that TDP-43 dimers may initiate or “seed” the formation of high molecular weight pathologic TDP-43 aggregates[17]

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