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Neuron. 2019 Apr 17;102(2):321-338.e8. doi: 10.1016/j.neuron.2019.01.048. Epub 2019 Feb 27.

RNA Binding Antagonizes Neurotoxic Phase Transitions of TDP-43.

Author information

1
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA.
2
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA.
3
Department of Biochemistry and Biophysics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
4
Department of Biological Sciences, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
5
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA.
6
LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15213, USA.
7
LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA; Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
8
Department of Biological Sciences, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Protein Conformational Diseases, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA.
9
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA; LiveLikeLou Center for ALS Research, University of Pittsburgh Brain Institute, Pittsburgh, PA 15213, USA; Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15213, USA; Center for Protein Conformational Diseases, Kenneth P. Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: chrisdonnelly@pitt.edu.

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

PMID:
30826182
PMCID:
PMC6472983
[Available on 2020-04-17]
DOI:
10.1016/j.neuron.2019.01.048

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