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Mechanisms Associated with TDP-43 Neurotoxicity in ALS/FTLD

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RNA Metabolism in Neurodegenerative Diseases

Part of the book series: Advances in Neurobiology ((NEUROBIOL,volume 20))

Abstract

The discovery of TDP-43 as a major disease protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) was first made in 2006. Prior to 2006 there were only 11 publications related to TDP-43, now there are over 2000, indicating the importance of TDP-43 to unraveling the complex molecular mechanisms that underpin the pathogenesis of ALS/FTLD. Subsequent to this discovery, TDP-43 pathology was also found in other neurodegenerative diseases, including Alzheimer’s disease, the significance of which is still in the early stages of exploration. TDP-43 is a predominantly nuclear DNA/RNA-binding protein, one of a number of RNA-binding proteins that are now known to be linked with ALS/FTLD, including Fused in Sarcoma (FUS), heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), and heterogeneous nuclear ribonucleoprotein A2/B1 (hnRNP A2/B1). However, what sets TDP-43 apart is the vast number of cases in which TDP-43 pathology is present, providing a point of convergence, the understanding of which could lead to broadly applicable therapeutics. Here we will focus on TDP-43 in ALS/FTLD, its nuclear and cytoplasmic functions, and consequences should these functions go awry.

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Authors and Affiliations

  1. Tanz Centre for Research in Neurodegenerative Diseases and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5T 2S8, Canada

    Marc Shenouda, Ashley B. Zhang, Anna Weichert & Janice Robertson

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  1. Marc Shenouda
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  2. Ashley B. Zhang
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  3. Anna Weichert
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  4. Janice Robertson
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Correspondence to Janice Robertson .

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  1. Department of Neurobiology and Neurology, Dignityhealth St. Joseph’s Hospital, Barrow Neurological Institute, Phoenix, Arizona, USA

    Rita Sattler

  2. Department of Neurobiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Christopher J. Donnelly

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Shenouda, M., Zhang, A.B., Weichert, A., Robertson, J. (2018). Mechanisms Associated with TDP-43 Neurotoxicity in ALS/FTLD. In: Sattler, R., Donnelly, C. (eds) RNA Metabolism in Neurodegenerative Diseases. Advances in Neurobiology, vol 20. Springer, Cham. https://doi.org/10.1007/978-3-319-89689-2_9

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