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, 102 (2), 321-338.e8

RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43

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RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43

Jacob R Mann et al. Neuron.

Abstract

TDP-43 proteinopathy is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia where cytoplasmic TDP-43 inclusions are observed within degenerating regions of patient postmortem tissue. The mechanism by which TDP-43 aggregates has remained elusive due to technological limitations, which prevent the analysis of specific TDP-43 interactions in live cells. We present an optogenetic approach to reliably induce TDP-43 proteinopathy under spatiotemporal control. We show that the formation of pathologically relevant inclusions is driven by aberrant interactions between low-complexity domains of TDP-43 that are antagonized by RNA binding. Although stress granules are hypothesized to be a conduit for seeding TDP-43 proteinopathy, we demonstrate pathological inclusions outside these RNA-rich structures. Furthermore, we show that aberrant phase transitions of cytoplasmic TDP-43 are neurotoxic and that treatment with oligonucleotides composed of TDP-43 target sequences prevent inclusions and rescue neurotoxicity. Collectively, these studies provide insight into the mechanisms that underlie TDP-43 proteinopathy and present a potential avenue for therapeutic intervention.

Keywords: ALS; FTD; LLPS; RBP; RNA binding protein; TDP-43; bait oligonucleotide; liquid-liquid phase separation; neurodegeneration; optoTDP43; proteinopathy; stress granule.

Conflict of interest statement

Competing Interests

No competing financial interests to declare. Dr. Christopher Donnelly and Jacob Mann are inventors of intellectual property described in this manuscript and submitted as provisional patents by the University of Pittsburgh.

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