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Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy

Author

Listed:
  • Sabrina Villar-Pazos

    (University of Pittsburgh School of Medicine
    Vienna Biocenter Campus (VBC))

  • Laurel Thomas

    (University of Pittsburgh School of Medicine)

  • Yunhan Yang

    (University of Pittsburgh School of Medicine)

  • Kun Chen

    (University of Pittsburgh School of Medicine
    Tongji Medical College, Huazhong University of Science and Technology)

  • Jenea B. Lyles

    (University of Pittsburgh School of Medicine)

  • Bradley J. Deitch

    (University of Pittsburgh School of Medicine)

  • Joseph Ochaba

    (Ionis Pharmaceuticals)

  • Karen Ling

    (Ionis Pharmaceuticals)

  • Berit Powers

    (Ionis Pharmaceuticals)

  • Sebastien Gingras

    (University of Pittsburgh School of Medicine)

  • Holly B. Kordasiewicz

    (Ionis Pharmaceuticals)

  • Melanie J. Grubisha

    (University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine)

  • Yanhua H. Huang

    (University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine)

  • Gary Thomas

    (University of Pittsburgh School of Medicine)

Abstract

PACS1 syndrome is a neurodevelopmental disorder (NDD) caused by a recurrent de novo missense mutation in PACS1 (p.Arg203Trp (PACS1R203W)). The mechanism by which PACS1R203W causes PACS1 syndrome is unknown, and no curative treatment is available. Here, we use patient cells and PACS1 syndrome mice to show that PACS1 (or PACS-1) is an HDAC6 effector and that the R203W substitution increases the PACS1/HDAC6 interaction, aberrantly potentiating deacetylase activity. Consequently, PACS1R203W reduces acetylation of α-tubulin and cortactin, causing the Golgi ribbon in hippocampal neurons and patient-derived neural progenitor cells (NPCs) to fragment and overpopulate dendrites, increasing their arborization. The dendrites, however, are beset with varicosities, diminished spine density, and fewer functional synapses, characteristic of NDDs. Treatment of PACS1 syndrome mice or patient NPCs with PACS1- or HDAC6-targeting antisense oligonucleotides, or HDAC6 inhibitors, restores neuronal structure and synaptic transmission in prefrontal cortex, suggesting that targeting PACS1R203W/HDAC6 may be an effective therapy for PACS1 syndrome.

Suggested Citation

  • Sabrina Villar-Pazos & Laurel Thomas & Yunhan Yang & Kun Chen & Jenea B. Lyles & Bradley J. Deitch & Joseph Ochaba & Karen Ling & Berit Powers & Sebastien Gingras & Holly B. Kordasiewicz & Melanie J. , 2023. "Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42176-8
    DOI: 10.1038/s41467-023-42176-8
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