The role of FUS gene variants in neurodegenerative diseases

Journal name:
Nature Reviews Neurology
Volume:
10,
Pages:
337–348
Year published:
DOI:
doi:10.1038/nrneurol.2014.78
Published online

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.

At a glance

Figures

  1. Schematic representation of the FUS transcript, and functional domains of the FUS protein with gene mutations identified in patients with neurodegenerative diseases.
    Figure 1: Schematic representation of the FUS transcript, and functional domains of the FUS protein with gene mutations identified in patients with neurodegenerative diseases.

    FUS has 526 amino acids and contains several conserved domains: SYGQ, RGG, RRM, E, L and ZnF. Numbers under the protein line indicate the boundaries of each domain. The putative prion domain of FUS comprises amino acids 1–239 and 391–407. *The pathogenicity of many mutations identified in patients with FTLD still needs to be validated. Mutations identified in patients with ALS and FTLD, or in their families. §Mutations identified in patients with ALS, and in those with essential tremor. ||Mutations identified in patients with essential tremor. Mutations identified in patients with ALS, and in those with both ALS and FTLD. Abbreviations: ALS, amyotrophic lateral sclerosis; E, nuclear export signal; FTLD, frontotemporal lobar degeneration; L, nuclear localization signal; RGG, Arg–Gly–Gly-rich motifs; RRM, RNA-recognition motif; SYGQ, Ser–Tyr–Gly–Gln; ZnF, zinc-finger motif.

  2. Subcellular distribution, seeding aggregation and prion-like transmission of FUS.
    Figure 2: Subcellular distribution, seeding aggregation and prion-like transmission of FUS.

    Normal FUS is a primarily nuclear, RNA-binding protein (1). Mutant FUS proteins have a disrupted NLS and are, therefore, mainly mislocalized to the cytoplasm (although the RNA-binding domain of mutant FUS can be localized to the nucleus and the cytoplasm). Cellular stress induces expression of FUS, which targets RNAs for incorporation into stress granules in the cytoplasm (2). When stress resolves, the stress granules rapidly dissociate and release sequestered RNAs and FUS protein, which resume their normal function. The RNA-binding domain of mutant FUS protein cannot be incorporated into stress granules. Sustained cellular stress, therefore, encourages aggregation of mutant FUS and/or impairs disassembly of stress granules, which might facilitate irreversible FUS aggregation (3). Cell-to-cell, prion-like transmission of these FUS aggregates might lead to disease phenotypes. Abbreviation: NLS, nuclear localization signal.

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Affiliations

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

    • Hao Deng &
    • Kai Gao
  2. Department of Neurology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.

    • Joseph Jankovic

Contributions

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.

Competing interests statement

The authors declare no competing interests.

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  • Hao Deng

    Professor Hao Deng is the Executive Vice Director of the Center for Experimental Medicine and the Conjunct Professor of the Department of Neurology, the Third Xiangya Hospital, Central South University, Changsha, Huanan, China. He earned his medical degree and completed his training in the State Key Laboratory of Medical Genetics at Central South University, Changsha, Huanan, China. He is actively involved in basic research, focusing on the mechanisms of hereditary diseases, and he has a special interest in neurological disorders.

  • Kai Gao

    Kai Gao is a graduate student in Center for Experimental Medicine at the Third Xiangya Hospital, Central South University, Changsha, Huanan, China. His research is focused on molecular genetics and mechanisms of neurological diseases. He obtained his Bachelors degree from the Xiangya Medical School of Central South University, Changsha, Huanon, China.

  • Joseph Jankovic

    Joseph Jankovic is a professor in the Department of Neurology, the Distinguished Chair in Movement Disorders, and the director of the Parkinson's Disease Center and Movement Disorders Clinic at Baylor College of Medicine, Houston, TX, USA. He leads a research group that focuses on determining the aetiology and pathophysiology of movement disorders. He is also a member of numerous scientific and medical advisory boards of national foundations including Awareness for Movement Disorders, the Dystonia Medical Research Foundation, the International Tremor Foundation, the Tourette Syndrome Association, and the World Federation of Neurology Research Committee on Parkinson's Disease and Related Disorders.

Supplementary information

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  1. Supplementary Table 1 (154 KB)

    Summary of clinical and genetic features of ALS patients with FUS mutations

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