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

• DOI: 10.1038/s41467-017-00062-0
• Publication Date: 2017-06-22T16:41:20Z
• Authors: Tariq Afroz; Eva-Maria Hock; Patrick Ernst; Chiara Foglieni; Melanie Jambeau; Larissa A. B. Gil...; Florent Laferriere; Zuzanna Maniecka; Andreas Plückthun; Peer Mittl; Paolo Paganetti; Frédéric H. T. Al...; Magdalini Polymen...
• Keywords: Stress granule

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