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Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates that reduce surface AMPA receptor expression in primary neurons

View ORCID ProfileJocelyn Widagdo, Saumya Udagedara, View ORCID ProfileNishita Bhembre, View ORCID ProfileJing Zhi Anson Tan, Lara Neureiter, Jie Huang, View ORCID ProfileVictor Anggono, View ORCID ProfileMihwa Lee
doi: https://doi.org/10.1101/2022.03.10.483757
Jocelyn Widagdo
1Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
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  • ORCID record for Jocelyn Widagdo
Saumya Udagedara
2Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
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Nishita Bhembre
1Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
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Jing Zhi Anson Tan
1Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
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Lara Neureiter
1Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
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Jie Huang
2Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
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Victor Anggono
1Clem Jones Centre for Ageing Dementia Research, Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
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  • For correspondence: mihwa.lee@latrobe.edu.au v.anggono@uq.edu.au
Mihwa Lee
2Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria 3086, Australia
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  • For correspondence: mihwa.lee@latrobe.edu.au v.anggono@uq.edu.au
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ABSTRACT

SFPQ is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated SFPQ variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating center (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a secondary zinc-binding site revealed by the 1.83Å crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Funding This study was supported by grants from the Motor Neurone Disease Research Australia (the Judy Mitchell MND Research Grant) to VA, ML and JW, and the Australian Medical Research Future Fund (Clem Jones Centre for Ageing Dementia Research Flagship Project Grant) to VA. ML holds a Tracey Banivanua Mar Fellowship (La Trobe University). JW holds a University of Queensland (UQ) Amplify Fellowship. JZAT was supported by a UQ Researcher Retention (RSA2) Fellowship. JH was the recipient of a PhD scholarship from La Trobe University.

  • Conflict of interest The authors declare no conflict of interests.

  • Ethical Approval All animal handling procedures were carried out in accordance with the Australian Code of Practice for the Care and Use of Animals for Scientific Purposes and were approved by the University of Queensland Animal Ethics Committee (AEC approval number QBI/047/18).

  • Informed Consent This article does not contain any studies with human participants performed by any of the authors. All authors have read and agreed with the submission of the manuscript.

  • Data Availability Atomic coordinates and structure factors for the reported crystal structures have been deposited with the Protein Data Bank under the accession number 7SP0.

  • Abbreviations

    ALS
    amyotrophic lateral sclerosis
    AMPA
    α-amino-3-hydroxy-5-methyl-4- isoxazoleproprionic acid
    AMPAR
    AMPA receptor
    DBHS
    Drosophila behavior human splicing
    fALS
    familial ALS
    FUS
    fused in sarcoma
    RBP
    RNA-binding protein
    r.m.s.d.
    root mean square deviation
    RRM
    RNA-recognition motif
    RXRα
    retinoic X receptor α
    SFPQ
    splicing factor proline- and glutamine-rich
    TDP-43
    trans-activation response element DNA-binding protein 43
    WT
    wild-type.
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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    Posted March 12, 2022.
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    Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates that reduce surface AMPA receptor expression in primary neurons
    Jocelyn Widagdo, Saumya Udagedara, Nishita Bhembre, Jing Zhi Anson Tan, Lara Neureiter, Jie Huang, Victor Anggono, Mihwa Lee
    bioRxiv 2022.03.10.483757; doi: https://doi.org/10.1101/2022.03.10.483757
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    Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates that reduce surface AMPA receptor expression in primary neurons
    Jocelyn Widagdo, Saumya Udagedara, Nishita Bhembre, Jing Zhi Anson Tan, Lara Neureiter, Jie Huang, Victor Anggono, Mihwa Lee
    bioRxiv 2022.03.10.483757; doi: https://doi.org/10.1101/2022.03.10.483757

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