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  • Review Article
  • Published:

The role of FUS gene variants in neurodegenerative diseases

Nature Reviews Neurology volume 10, pages 337–348 (2014)Cite this article

Subjects

Key Points

  • Variants in the FUS gene are causative or risk factors for several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and essential tremor

  • Abnormal aggregation of the FUS protein has been reported in ALS, FTLD and polyglutamine diseases, suggesting an important role for this protein pathology in neurodegenerative diseases

  • Under physiological conditions, FUS is mainly found in the nuclear compartment, where it is involved in the regulation of various cellular processes

  • In neurodegenerative diseases, FUS is primarily found in cytoplasmic inclusions that have variable morphology and distribution across distinct disease entities

  • Functional and animal studies have led to improved understanding of the pathogenetic mechanisms of FUS-related disorders; the results identify this protein as a promising therapeutic target

Abstract

The neurodegenerative diseases are a diverse group of disorders characterized by progressive loss of specific groups of neurons. These diseases affect different populations, and have a variable age of onset, clinical symptoms, and pathological findings. Variants in the FUS gene, which encodes an RNA-binding protein, have been identified as causative or risk factors for amyotrophic lateral sclerosis (ALS), essential tremor and rare forms of frontotemporal lobar degeneration (FTLD). Additionally, abnormal aggregation of FUS protein has been reported in multiple neurodegenerative diseases, including ALS, FTLD and the polyglutamine diseases, suggesting a role for FUS in the pathogenesis of these neurodegenerative diseases. This Review summarizes current understanding of the normal function of FUS, and describes its role in the pathology of ALS, FTLD, essential tremor and other neurodegenerative diseases. Comments on the underlying pathogenetic mechanisms of these FUS-related disorders are included. Finally, the clinical implications of recent advances in FUS research are discussed. Further understanding of the role of FUS in neurodegenerative diseases might lead to improvements in the treatment and prevention of these disorders.

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Figure 1: Schematic representation of the FUS transcript, and functional domains of the FUS protein with gene mutations identified in patients with neurodegenerative diseases.
Figure 2: Subcellular distribution, seeding aggregation and prion-like transmission of FUS.

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Acknowledgements

H.D.'s research was funded by National Natural Science Foundation of China (81271921, 81101339), the Sheng Hua Scholars Program of Central South University, the Fundamental Research Funds for the Central Universities (2011JQ014), Research Fund for the Doctoral Program of Higher Education of China (20110162110,026), and the Construction Fund for Key Subjects of the Third Xiangya Hospital, Central South University. K.G.'s research was supported by the Fundamental Research Funds for the Central Universities of Central South University (2012zzts120). J.J. receives support from the National Parkinson Foundation.

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  1. Centre for Experimental Medicine and Department of Neurology, Third Xiangya Hospital, Central South University, 138 Tongzipo Road, Changsha, 410013, Hunan, China

    Hao Deng & Kai Gao

  2. Department of Neurology, Baylor College of Medicine, 1 Baylor Plaza, Houston, 77030, TX, USA

    Joseph Jankovic

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H.D. and K.G. contributed equally to researching data for the article, discussions of the content, and writing the article. J.J. contributed to review and editing of the manuscript before submission.

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Supplementary Table 1

Summary of clinical and genetic features of ALS patients with FUS mutations (DOC 154 kb)

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Deng, H., Gao, K. & Jankovic, J. The role of FUS gene variants in neurodegenerative diseases. Nat Rev Neurol 10, 337–348 (2014). https://doi.org/10.1038/nrneurol.2014.78

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