Dynamic polymerization of TDP-43 in health and disease
published: July 21, 2017, recorded: May 2017, views: 908
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TDP-43 is a primarily nuclear RNA-binding protein (RBP), whose abnormal phosphorylation and cytoplasmic aggregation characterizes affected neurons in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Even though the loss of normal nuclear localization and cytoplasmic TDP- 43 aggregation correlates with neurodegeneration, the exact mechanisms of neurotoxicity remain elusive. Moreover, the molecular mechanisms triggering TDP-43 pathology in ALS and FTD remain poorly understood, in part due to lack of high-resolution structural information of TDP-43 in the physiological as well as pathological state. Here we report that physiological TDP-43 exists as nuclear oligomers that are distinct from cytoplasmic complexes formed upon cellular stress or pathologic aggregates. To elucidate the molecular basis of physiological TDP- 43 oligomerization, we determined the crystal structure of TDP-43 NTD at 2.1-Å resolution, which revealed an unprecedented mode of head-to-tail interactions between monomers generating solenoid-like polymers (1). Consistent with the crystal structure, solution NMR spectroscopy confirmed the dynamic nature of inter- molecular and low micromolar affinity electrostatic interactions that stabilize these polymers (1). Destabilizing oligomerization by point mutations resulted in loss of TDP-43 regulation of alternative splicing of known neuronal RNA targets, indicating that these dynamic TDP-43 oligomers are the functional form of the protein in vivo (1). Tripartite GFP complementation experiments in cells illustrate that physiological TDP-43 oligomerization prevents low complexity domain intermolecular interactions (1). Importantly, we show that NTD-driven TDP-43 oligomerization antagonizes pathologic aggregation. This dynamic head-to-tail polymerization of TDP-43 is unique among RBPs and broadens our understanding of TDP-43 function. Most excitingly, our findings indicate that stabilization of functional TDP-43 oligomers could have therapeutic potential by counteracting pathologic aggregation and restoring nuclear function.
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