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

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. Grubisha, Yanhua H. Huang and Gary Thomas ()
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Sabrina Villar-Pazos: University of Pittsburgh School of Medicine
Laurel Thomas: University of Pittsburgh School of Medicine
Yunhan Yang: University of Pittsburgh School of Medicine
Kun Chen: University of Pittsburgh School of Medicine
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
Yanhua H. Huang: University of Pittsburgh School of Medicine
Gary Thomas: University of Pittsburgh School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42176-8

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