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

Tariq Afroz, Eva-Maria Hock, Patrick Ernst, Chiara Foglieni, Melanie Jambeau, Larissa A. B. Gilhespy, Florent Laferriere, Zuzanna Maniecka, Andreas Plückthun, Peer Mittl, Paolo Paganetti, Frédéric H. T. Allain and Magdalini Polymenidou ()
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Tariq Afroz: University of Zurich
Eva-Maria Hock: University of Zurich
Patrick Ernst: University of Zurich
Chiara Foglieni: Neurocenter of Southern Switzerland
Melanie Jambeau: University of Zurich
Larissa A. B. Gilhespy: University of Zurich
Florent Laferriere: University of Zurich
Zuzanna Maniecka: University of Zurich
Andreas Plückthun: University of Zurich
Peer Mittl: University of Zurich
Paolo Paganetti: Neurocenter of Southern Switzerland
Frédéric H. T. Allain: Institute of Molecular Biology and Biophysics
Magdalini Polymenidou: University of Zurich

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

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00062-0

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