IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-44989-7.html
   My bibliography  Save this article

iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity

Author

Listed:
  • Lauren Rylaarsdam

    (Northwestern University)

  • Jennifer Rakotomamonjy

    (Northwestern University)

  • Eleanor Pope

    (Northwestern University)

  • Alicia Guemez-Gamboa

    (Northwestern University)

Abstract

PACS1 syndrome is a neurodevelopmental disorder characterized by intellectual disability and distinct craniofacial abnormalities resulting from a de novo p.R203W variant in phosphofurin acidic cluster sorting protein 1 (PACS1). PACS1 is known to have functions in the endosomal pathway and nucleus, but how the p.R203W variant affects developing neurons is not fully understood. Here we differentiated stem cells towards neuronal models including cortical organoids to investigate the impact of the PACS1 syndrome-causing variant on neurodevelopment. While few deleterious effects were detected in PACS1(+/R203W) neural precursors, mature PACS1(+/R203W) glutamatergic neurons exhibited impaired expression of genes involved in synaptic signaling processes. Subsequent characterization of neural activity using calcium imaging and multielectrode arrays revealed the p.R203W PACS1 variant leads to a prolonged neuronal network burst duration mediated by an increased interspike interval. These findings demonstrate the impact of the PACS1 p.R203W variant on developing human neural tissue and uncover putative electrophysiological underpinnings of disease.

Suggested Citation

  • Lauren Rylaarsdam & Jennifer Rakotomamonjy & Eleanor Pope & Alicia Guemez-Gamboa, 2024. "iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44989-7
    DOI: 10.1038/s41467-024-44989-7
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-44989-7
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-44989-7?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Aparna Bhaduri & Madeline G. Andrews & Walter Mancia Leon & Diane Jung & David Shin & Denise Allen & Dana Jung & Galina Schmunk & Maximilian Haeussler & Jahan Salma & Alex A. Pollen & Tomasz J. Nowako, 2020. "Cell stress in cortical organoids impairs molecular subtype specification," Nature, Nature, vol. 578(7793), pages 142-148, February.
    2. Hsiao-Tuan Chao & Hongmei Chen & Rodney C. Samaco & Mingshan Xue & Maria Chahrour & Jong Yoo & Jeffrey L. Neul & Shiaoching Gong & Hui-Chen Lu & Nathaniel Heintz & Marc Ekker & John L. R. Rubenstein &, 2010. "Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes," Nature, Nature, vol. 468(7321), pages 263-269, November.
    3. T. Karayannis & E. Au & J. C. Patel & I. Kruglikov & S. Markx & R. Delorme & D. Héron & D. Salomon & J. Glessner & S. Restituito & A. Gordon & L. Rodriguez-Murillo & N. C. Roy & J. A. Gogos & B. Rudy , 2014. "Cntnap4 differentially contributes to GABAergic and dopaminergic synaptic transmission," Nature, Nature, vol. 511(7508), pages 236-240, July.
    4. Marc P. Forrest & Marc Dos Santos & Nicolas H. Piguel & Yi-Zhi Wang & Nicole A. Hawkins & Vikram A. Bagchi & Leonardo E. Dionisio & Sehyoun Yoon & Dina Simkin & Maria Dolores Martin-de-Saavedra & Ruoq, 2023. "Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    5. Goichi Miyoshi & Yoshifumi Ueta & Akiyo Natsubori & Kou Hiraga & Hironobu Osaki & Yuki Yagasaki & Yusuke Kishi & Yuchio Yanagawa & Gord Fishell & Robert P. Machold & Mariko Miyata, 2021. "FoxG1 regulates the formation of cortical GABAergic circuit during an early postnatal critical period resulting in autism spectrum disorder-like phenotypes," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    6. Maria Sundberg & Hannah Pinson & Richard S. Smith & Kellen D. Winden & Pooja Venugopal & Derek J. C. Tai & James F. Gusella & Michael E. Talkowski & Christopher A. Walsh & Max Tegmark & Mustafa Sahin, 2021. "16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    7. Fikri Birey & Jimena Andersen & Christopher D. Makinson & Saiful Islam & Wu Wei & Nina Huber & H. Christina Fan & Kimberly R. Cordes Metzler & Georgia Panagiotakos & Nicholas Thom & Nancy A. O’Rourke , 2017. "Assembly of functionally integrated human forebrain spheroids," Nature, Nature, vol. 545(7652), pages 54-59, May.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Yueqi Wang & Simone Chiola & Guang Yang & Chad Russell & Celeste J. Armstrong & Yuanyuan Wu & Jay Spampanato & Paisley Tarboton & H. M. Arif Ullah & Nicolas U. Edgar & Amelia N. Chang & David A. Harmi, 2022. "Modeling human telencephalic development and autism-associated SHANK3 deficiency using organoids generated from single neural rosettes," Nature Communications, Nature, vol. 13(1), pages 1-25, December.
    2. Anna Pagliaro & Roxy Finger & Iris Zoutendijk & Saskia Bunschuh & Hans Clevers & Delilah Hendriks & Benedetta Artegiani, 2023. "Temporal morphogen gradient-driven neural induction shapes single expanded neuroepithelium brain organoids with enhanced cortical identity," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    3. Tatsuya Osaki & Tomoya Duenki & Siu Yu A. Chow & Yasuhiro Ikegami & Romain Beaubois & Timothée Levi & Nao Nakagawa-Tamagawa & Yoji Hirano & Yoshiho Ikeuchi, 2024. "Complex activity and short-term plasticity of human cerebral organoids reciprocally connected with axons," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    4. Yu-Jun Wang & Gui-Ying Zan & Cenglin Xu & Xue-Ping Li & Xuelian Shu & Song-Yu Yao & Xiao-Shan Xu & Xiaoyun Qiu & Yexiang Chen & Kai Jin & Qi-Xin Zhou & Jia-Yu Ye & Yi Wang & Lin Xu & Zhong Chen & Jing, 2023. "The claustrum-prelimbic cortex circuit through dynorphin/κ-opioid receptor signaling underlies depression-like behaviors associated with social stress etiology," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Xin-Yan Zhang & Karen Spruyt, 2022. "Literature Cases Summarized Based on Their Polysomnographic Findings in Rett Syndrome," IJERPH, MDPI, vol. 19(6), pages 1-17, March.
    6. Elaine T. Lim & Yingleong Chan & Pepper Dawes & Xiaoge Guo & Serkan Erdin & Derek J. C. Tai & Songlei Liu & Julia M. Reichert & Mannix J. Burns & Ying Kai Chan & Jessica J. Chiang & Katharina Meyer & , 2022. "Orgo-Seq integrates single-cell and bulk transcriptomic data to identify cell type specific-driver genes associated with autism spectrum disorder," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    7. Julien G. Roth & Lucia G. Brunel & Michelle S. Huang & Yueming Liu & Betty Cai & Sauradeep Sinha & Fan Yang & Sergiu P. Pașca & Sungchul Shin & Sarah C. Heilshorn, 2023. "Spatially controlled construction of assembloids using bioprinting," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Yanmei Zhang & Qifan Hu & Yuquan Pei & Hao Luo & Zixuan Wang & Xinxin Xu & Qing Zhang & Jianli Dai & Qianqian Wang & Zilian Fan & Yongcong Fang & Min Ye & Binhan Li & Mailin Chen & Qi Xue & Qingfeng Z, 2024. "A patient-specific lung cancer assembloid model with heterogeneous tumor microenvironments," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    9. M. Angeles Rabadan & Estanislao Daniel De La Cruz & Sneha B. Rao & Yannan Chen & Cheng Gong & Gregg Crabtree & Bin Xu & Sander Markx & Joseph A. Gogos & Rafael Yuste & Raju Tomer, 2022. "An in vitro model of neuronal ensembles," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    10. Fabio Papes & Antonio P. Camargo & Janaina S. Souza & Vinicius M. A. Carvalho & Ryan A. Szeto & Erin LaMontagne & José R. Teixeira & Simoni H. Avansini & Sandra M. Sánchez-Sánchez & Thiago S. Nakahara, 2022. "Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content," Nature Communications, Nature, vol. 13(1), pages 1-26, December.
    11. Ya-Nan Zhao & Jian-Bo Jiang & Shi-Yuan Tao & Yang Zhang & Ze-Ka Chen & Wei-Min Qu & Zhi-Li Huang & Su-Rong Yang, 2022. "GABAergic neurons in the rostromedial tegmental nucleus are essential for rapid eye movement sleep suppression," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    12. Hannah Drew Rickner & Lulu Jiang & Rui Hong & Nicholas K. O’Neill & Chromewell A. Mojica & Benjamin J. Snyder & Lushuang Zhang & Dipan Shaw & Maria Medalla & Benjamin Wolozin & Christine S. Cheng, 2022. "Single cell transcriptomic profiling of a neuron-astrocyte assembloid tauopathy model," Nature Communications, Nature, vol. 13(1), pages 1-22, December.
    13. Tal Sharf & Tjitse Molen & Stella M. K. Glasauer & Elmer Guzman & Alessio P. Buccino & Gabriel Luna & Zhuowei Cheng & Morgane Audouard & Kamalini G. Ranasinghe & Kiwamu Kudo & Srikantan S. Nagarajan &, 2022. "Functional neuronal circuitry and oscillatory dynamics in human brain organoids," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    14. Maisumu Gulimiheranmu & Shuang Li & Junmei Zhou, 2021. "In Vitro Recapitulation of Neuropsychiatric Disorders with Pluripotent Stem Cells-Derived Brain Organoids," IJERPH, MDPI, vol. 18(23), pages 1-14, November.
    15. Matthew C. Pahl & Claudia A. Doege & Kenyaita M. Hodge & Sheridan H. Littleton & Michelle E. Leonard & Sumei Lu & Rick Rausch & James A. Pippin & Maria Caterina Rosa & Alisha Basak & Jonathan P. Bradf, 2021. "Cis-regulatory architecture of human ESC-derived hypothalamic neuron differentiation aids in variant-to-gene mapping of relevant complex traits," Nature Communications, Nature, vol. 12(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-44989-7. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.