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SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration

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Abstract

GEMIN5 is essential for core assembly of small nuclear Ribonucleoproteins (snRNPs), the building blocks of spliceosome formation. Loss-of-function mutations in GEMIN5 lead to a neurodevelopmental syndrome among patients presenting with developmental delay, motor dysfunction, and cerebellar atrophy by perturbing SMN complex protein expression and assembly. Currently, molecular determinants of GEMIN5-mediated disease have yet to be explored. Here, we identified SMN as a genetic suppressor of GEMIN5-mediated neurodegeneration in vivo. We discovered that an increase in SMN expression by either SMN gene therapy replacement or the antisense oligonucleotide (ASO), Nusinersen, significantly upregulated the endogenous levels of GEMIN5 in mammalian cells and mutant GEMIN5-derived iPSC neurons. Further, we identified a strong functional association between the expression patterns of SMN and GEMIN5 in patient Spinal Muscular Atrophy (SMA)-derived motor neurons harboring loss-of-function mutations in the SMN gene. Interestingly, SMN binds to the C-terminus of GEMIN5 and requires the Tudor domain for GEMIN5 binding and expression regulation. Finally, we show that SMN upregulation ameliorates defective snRNP biogenesis and alternative splicing defects caused by loss of GEMIN5 in iPSC neurons and in vivo. Collectively, these studies indicate that SMN acts as a regulator of GEMIN5 expression and neuropathologies.

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Data availability

The data that support the findings of this study are all included throughout the manuscript and available on request from the corresponding author.

Abbreviations

ALS:

Amyotrophic lateral sclerosis

ASO:

Antisense oligonucleotide

CB:

Cajal body

iPSC:

Induced pluripotent stem cell

SMA:

Spinal muscular atrophy

SMN:

Survival motor neuron

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Acknowledgements

The authors would like to thank Dr. Joseph Gall for gifting the Drosophila anti-coilin antibody. A.S. is supported by 1RO1EY032959-01 from NIH, Schuellein Chair Endowment Fund, and STEM Catalyst Grant from the University of Dayton.

Funding

This work was supported by the Children’s Neuroscience Institute Research grant (D.S.R. and U.B.P.), Children’s Hospital of Pittsburgh of the UPMC Health system (T.R.F.), and by the German Research Foundation [Wi 945/17–1 (ID 398410809), Wi 945/19–1 (ID 417989143), SFB1451 (ID 431549029), and GRK1960 (ID 233886668)], and the European Union’s Horizon 2020 Marie Skłodowska-Curie [ID 956185 (SMABEYOND] (B.W.).

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Author notes

  1. Tyler R. Fortuna and Sukhleen Kour have contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Tyler R. Fortuna, Sukhleen Kour, Eric N. Anderson, Charlie H. Nelson IV, Caroline Ward, Om Chauhan, Deepa S. Rajan & Udai Bhan Pandey

  2. Department of Biology, University of Dayton, Dayton, OH, USA

    Anuradha Venkatakrishnan Chimata & Amit Singh

  3. Department of Pediatrics, Division of Health Informatics, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Casey O’Brien & Dhivyaa Rajasundaram

  4. Institute of Human Genetics, Center for Molecular Medicine, Center for Rare Disorders, University of Cologne, Cologne, Germany

    Anixa Muiños-Bühl & Brunhilde Wirth

  5. Children’s Neuroscience Institute, Children’s Hospital of Pittsburgh, Pittsburgh, PA, USA

    Udai Bhan Pandey

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  1. Tyler R. Fortuna
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Contributions

Design of this study: T.R.F, S.K., A.V.C., A.M.B., E.N.A., A.S., and U.B.P.; bioinformatics and statistical analysis: T.R.F, S.K., O.C., C.O’B., and D.R.; wrote the manuscript: T.R.F., S.K., and U.B.P.; critically read and edited the manuscript: T.R.F., S.K., A.M.B., C.W., B.W., A.S., and U.B.P. All authors reviewed and approved the manuscript prior to submission.

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Correspondence to Udai Bhan Pandey.

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Fortuna, T.R., Kour, S., Chimata, A.V. et al. SMN regulates GEMIN5 expression and acts as a modifier of GEMIN5-mediated neurodegeneration. Acta Neuropathol 146, 477–498 (2023). https://doi.org/10.1007/s00401-023-02607-8

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