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

Autor: Fortuna TR; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Kour S; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Chimata AV; Department of Biology, University of Dayton, Dayton, OH, USA., Muiños-Bühl A; Institute of Human Genetics, Center for Molecular Medicine, Center for Rare Disorders, University of Cologne, Cologne, Germany., Anderson EN; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Nelson Iv CH; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Ward C; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Chauhan O; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., O'Brien C; Department of Pediatrics, Division of Health Informatics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA., Rajasundaram D; Department of Pediatrics, Division of Health Informatics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA., Rajan DS; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA., Wirth B; Institute of Human Genetics, Center for Molecular Medicine, Center for Rare Disorders, University of Cologne, Cologne, Germany., Singh A; Department of Biology, University of Dayton, Dayton, OH, USA., Pandey UB; Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. udai@pitt.edu.; Children's Neuroscience Institute, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA. udai@pitt.edu.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2023 Sep; Vol. 146 (3), pp. 477-498. Date of Electronic Publication: 2023 Jun 27.
DOI: 10.1007/s00401-023-02607-8
Abstrakt: 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.
(© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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