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Senataxin, A Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration

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RNA Metabolism in Neurodegenerative Diseases

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

Abstract

Senataxin (SETX) is a DNA-RNA helicase whose C-terminal region shows homology to the helicase domain of the yeast protein Sen1p. Genetic discoveries have established the importance of SETX for neural function, as recessive mutations in the SETX gene cause Ataxia with Oculomotor Apraxia type 2 (AOA2) (OMIM: 606002), which is the third most common form of recessive ataxia, after Friedreich’s ataxia and Ataxia-Telangiectasia. In addition, rare, dominant SETX mutations cause a juvenile-onset form of Amyotrophic Lateral Sclerosis (ALS), known as ALS4. SETX performs a number of RNA regulatory functions, including maintaining RNA transcriptome homeostasis. Over the last decade, altered RNA regulation and aberrant RNA-binding protein function have emerged as a central theme in motor neuron disease pathogenesis, with evidence suggesting that sporadic ALS disease pathology may overlap with the molecular pathology uncovered in familial ALS. Like other RNA processing proteins linked to ALS, the basis for SETX gain-of-function motor neuron toxicity remains ill-defined. Studies of yeast Sen1p and mammalian SETX protein have revealed a range of important RNA regulatory functions, including resolution of R-loops to permit transcription termination, and RNA splicing. Growing evidence suggests that SETX may represent an important genetic modifier locus for sporadic ALS. In cycling cells, SETX is found at nuclear foci during the S/G2 cell-cycle transition phase, and may function at sites of collision between components of the replisome and transcription machinery. While we do not yet know which SETX activities are most critical to neurodegeneration, our evolving understanding of SETX function will undoubtedly be crucial for not only understanding the role of SETX in ALS and ataxia disease pathogenesis, but also for delineating the mechanistic biology of fundamentally important molecular processes in the cell.

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Acknowledgments

Our SETX research is supported by a grant from the Robert Packard Center for ALS Research at the Johns Hopkins School of Medicine.

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Authors and Affiliations

  1. Department of Neurology, Duke University School of Medicine, Durham, NC, USA

    Craig L. Bennett & Albert R. La Spada

  2. Department of Neurobiology, Duke University School of Medicine, Durham, NC, USA

    Craig L. Bennett & Albert R. La Spada

  3. Department of Cell Biology, Duke University School of Medicine, Durham, NC, USA

    Craig L. Bennett & Albert R. La Spada

  4. Duke Center for Neurodegeneration & Neurotherapeutics, Duke University School of Medicine, Durham, NC, USA

    Albert R. La Spada

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Correspondence to Albert R. La Spada .

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Editors and Affiliations

  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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Bennett, C.L., La Spada, A.R. (2018). Senataxin, A Novel Helicase at the Interface of RNA Transcriptome Regulation and Neurobiology: From Normal Function to Pathological Roles in Motor Neuron Disease and Cerebellar Degeneration. 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_10

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