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An Intramolecular Salt Bridge Linking TDP43's RNA Recognition Motifs Dictates RNA Binding and TDP43-Dependent Neurodegeneration

70 Pages Posted: 22 Aug 2018 Sneak Peek Status: Published

See all articles by Brittany N. Flores

Brittany N. Flores

University of Michigan at Ann Arbor - Cellular and Molecular Biology Graduate Program

Xingli Li

University of Michigan at Ann Arbor - Department of Neurology

Jose Martinez

University of Michigan at Ann Arbor - Department of Pharmacology

Asim A. Beg

University of Michigan at Ann Arbor - Department of Pharmacology

Sami J. Barmada

University of Michigan at Ann Arbor - Cellular and Molecular Biology Graduate Program

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Abstract

The majority of individuals with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit neuronal cytoplasmic inclusions rich in the RNA binding protein TDP43. Even so, the relationship between TDP43’s RNA binding properties and neurodegeneration remain obscure. Here we show that engineered mutations disrupting a salt bridge between TDP43’s RNA recognition motifs interfere with nucleic acid binding and eliminate recognition of native TDP43 substrates. These same mutations dramatically destabilize TDP43, alter its subcellular localization and abrogate TDP43-dependent neurodegeneration. Worms harboring homologous TDP-1 mutations phenocopy knockout strains, confirming the necessity of the salt bridge residues for TDP43 function. Moreover, the accumulation of functional TDP43, but not RNA binding-deficient variants, disproportionately affects the abundance and splicing of transcripts encoding oxidative phosphorylation and ribosome components. These studies demonstrate the significance of the salt bridge in sustaining TDP43 stability and RNA binding specificity, factors that are crucial for neurodegeneration arising from TDP43 deposition in ALS and FTD.

Suggested Citation

Flores, Brittany N. and Li, Xingli and Martinez, Jose and Beg, Asim A. and Barmada, Sami J., An Intramolecular Salt Bridge Linking TDP43's RNA Recognition Motifs Dictates RNA Binding and TDP43-Dependent Neurodegeneration (2018). Available at SSRN: https://ssrn.com/abstract=3236488 or http://dx.doi.org/10.2139/ssrn.3236488
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Brittany N. Flores (Contact Author)

University of Michigan at Ann Arbor - Cellular and Molecular Biology Graduate Program

500 S. State Street
Ann Arbor, MI 48109
United States

Xingli Li

University of Michigan at Ann Arbor - Department of Neurology

Ann Arbor, MI 48109
United States

Jose Martinez

University of Michigan at Ann Arbor - Department of Pharmacology

500 S. State Street
Ann Arbor, MI 48109
United States

Asim A. Beg

University of Michigan at Ann Arbor - Department of Pharmacology

500 S. State Street
Ann Arbor, MI 48109
United States

Sami J. Barmada

University of Michigan at Ann Arbor - Cellular and Molecular Biology Graduate Program

500 S. State Street
Ann Arbor, MI 48109
United States

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