2. Academic Validation
  3. Neural deficits in a mouse model of PACS1 syndrome are corrected with PACS1- or HDAC6-targeting therapy

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

  • Nat Commun. 2023 Oct 17;14(1):6547. doi: 10.1038/s41467-023-42176-8.
Sabrina Villar-Pazos # 1 2,  Laurel Thomas # 1,  Yunhan Yang 1,  Kun Chen 1 3,  Jenea B Lyles 1,  Bradley J Deitch 1,  Joseph Ochaba 4,  Karen Ling 4,  Berit Powers 4,  Sebastien Gingras 5,  Holly B Kordasiewicz 4,  Melanie J Grubisha 6 7,  Yanhua H Huang 6 7,  Gary Thomas 8
Affiliations

Affiliations

  • 1 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA.
  • 2 Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), Vienna Biocenter Campus (VBC), Vienna, Austria.
  • 3 Department of Anesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
  • 4 Ionis Pharmaceuticals, Carlsbad, CA, USA.
  • 5 Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 6 Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 7 Translational Neuroscience Program, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
  • 8 Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15219, USA. thomasg@pitt.edu.
  • # Contributed equally.
PMID: 37848409 DOI: 10.1038/s41467-023-42176-8
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.

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