Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice

Ekaterina I. Mokhonova; Daniel Helzer; Ravinder Malik; Hafsa Mamsa; Jackson Walker; Mark Maslanka; Tess S. Fleser; Mohammad H. Afsharinia; Shiheng Liu; Johan Holmberg; Z. Hong Zhou; Eric J. Deeds; Kirk C. Hansen; Elizabeth M. McNally; Rachelle H. Crosbie

doi:10.1172/JCI187868

¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

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¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

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¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

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¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

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¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

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¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

Find articles by Maslanka, M. in: PubMed | Google Scholar

¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

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¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

Find articles by Afsharinia, M. in: PubMed | Google Scholar

¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

Find articles by Liu, S. in: PubMed | Google Scholar

¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

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¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

Find articles by Zhou, Z. in: PubMed | Google Scholar

¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

Find articles by Deeds, E. in: PubMed | Google Scholar

¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

Find articles by Hansen, K. in: PubMed | Google Scholar |

¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

Find articles by McNally, E. in: PubMed | Google Scholar

¹Department of Integrative Biology and Physiology, UCLA, Los Angeles, United States of America

²Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, United States of America

³Department of Microbiology, Immunology, and Molecular Genetics, UCLA, Los Angeles, United States of America

⁴Department of Integrative Biology and Physiology, UCLA, Los Angeles, Sweden

⁵Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, United States of America

⁶Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, United States of America

Find articles by Crosbie, R. in: PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI187868.
Copyright © 2025, Mokhonova et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published June 23, 2025 - Version history

The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well-established that genetic mutations that disrupt the structural integrity of DGC result in numerous muscular dystrophies, the three-dimensional structure of the complex has remained elusive. Two recent elegant cryoEM structures of DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25-kDa tetraspanin-like protein, anchors beta-dystroglycan to the beta-, gamma- and delta-sarcoglycan trimer, supporting biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in gamma-sarcoglycanopathies enabling substitution of gamma-sarcoglycan by its homolog, zeta-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that zeta-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protect the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.

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Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice

Ekaterina I. Mokhonova,¹ Daniel Helzer,¹ Ravinder Malik,¹ Hafsa Mamsa,¹ Jackson Walker,¹ Mark Maslanka,² Tess S. Fleser,¹ Mohammad H. Afsharinia,¹ Shiheng Liu,³ Johan Holmberg,¹ Z. Hong Zhou,⁵ Eric J. Deeds,¹ Kirk C. Hansen,² Elizabeth M. McNally,⁶ and Rachelle H. Crosbie¹

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Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice

Ekaterina I. Mokhonova,1 Daniel Helzer,1 Ravinder Malik,1 Hafsa Mamsa,1 Jackson Walker,1 Mark Maslanka,2 Tess S. Fleser,1 Mohammad H. Afsharinia,1 Shiheng Liu,3 Johan Holmberg,1 Z. Hong Zhou,5 Eric J. Deeds,1 Kirk C. Hansen,2 Elizabeth M. McNally,6 and Rachelle H. Crosbie1

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Ekaterina I. Mokhonova,¹ Daniel Helzer,¹ Ravinder Malik,¹ Hafsa Mamsa,¹ Jackson Walker,¹ Mark Maslanka,² Tess S. Fleser,¹ Mohammad H. Afsharinia,¹ Shiheng Liu,³ Johan Holmberg,¹ Z. Hong Zhou,⁵ Eric J. Deeds,¹ Kirk C. Hansen,² Elizabeth M. McNally,⁶ and Rachelle H. Crosbie¹