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TDP-43 and Cytoskeletal Proteins in ALS

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Abstract

Amyotrophic lateral sclerosis (ALS) represents a rapidly progressing neurodegenerative disease and is characterized by a degeneration of motor neurons. Motor neurons are particularly susceptible to selective and early degeneration because of their extended axon length and their dependency on the cytoskeleton for its stability, signaling, and axonal transport. The motor neuron cytoskeleton comprises actin filaments, neurofilaments like peripherin, and microtubules. The Transactivating Response Region (TAR) DNA Binding Protein (TDP-43) forms characteristic cytoplasmic aggregates in motor neurons of ALS patients, and at least in part, the pathogenesis of ALS seems to be driven by toxic pTDP-43 aggregates in cytoplasm, which lead to a diminished axon formation and reduced axon length. Diminished axon formation and reduced axon length suggest an interaction of TDP-43 with the cytoskeleton of motor neurons. TDP-43 interacts with several cytoskeletal components, e.g., the microtubule-associated protein 1B (MAP1B) or the neurofilament light chain (NFL) through direct binding to its RNA. From a clinical perspective, cytoskeletal biomarkers like phosphorylated neurofilament heavy chain (pNFH) and NFL are already clinically used in ALS patients to predict survival, disease progression, and duration. Thus, in this review, we focus on the interaction of TDP-43 with the different cytoskeleton components such as actin filaments, neurofilaments, and microtubules as well as their associated proteins as one aspect in the complex pathogenesis of ALS.

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Acknowledgements

We acknowledge the financial support of an ALS Young Investigator Research Scholarship by the Deutsche Gesellschaft für Muskelkranke (DGM) (to M.O.) and EU funds (EFRE; SAB, 100111005; to M.H.).

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Authors and Affiliations

  1. Department of Neurology, University of Leipzig, Liebigstraße 20, 04103, Leipzig, Germany

    Moritz Oberstadt & Joseph Claßen

  2. Department for Molecular and Cellular Mechanisms of Neurodegeneration, Paul Flechsig Institute for Brain Research, University of Leipzig, Liebigstraße 19, 04103, Leipzig, Germany

    Thomas Arendt & Max Holzer

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  1. Moritz Oberstadt
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  2. Joseph Claßen
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  3. Thomas Arendt
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  4. Max Holzer
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Correspondence to Moritz Oberstadt.

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Oberstadt, M., Claßen, J., Arendt, T. et al. TDP-43 and Cytoskeletal Proteins in ALS. Mol Neurobiol 55, 3143–3151 (2018). https://doi.org/10.1007/s12035-017-0543-1

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