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CryoET reveals organelle phenotypes in huntington disease patient iPSC-derived and mouse primary neurons

Author

Listed:
  • Gong-Her Wu

    (Stanford University)

  • Charlene Smith-Geater

    (Department of Psychiatry & Human Behavior University of California Irvine)

  • Jesús G. Galaz-Montoya

    (Stanford University)

  • Yingli Gu

    (University of California San Diego)

  • Sanket R. Gupte

    (Stanford University)

  • Ranen Aviner

    (Stanford University)

  • Patrick G. Mitchell

    (Stanford University)

  • Joy Hsu

    (Stanford University)

  • Ricardo Miramontes

    (University of California Irvine)

  • Keona Q. Wang

    (University of California Irvine)

  • Nicolette R. Geller

    (University of California Irvine)

  • Cathy Hou

    (Stanford University)

  • Cristina Danita

    (Stanford University)

  • Lydia-Marie Joubert

    (Stanford University)

  • Michael F. Schmid

    (Stanford University)

  • Serena Yeung

    (Stanford University
    Stanford University)

  • Judith Frydman

    (Stanford University
    Stanford University)

  • William Mobley

    (University of California San Diego)

  • Chengbiao Wu

    (University of California San Diego)

  • Leslie M. Thompson

    (Department of Psychiatry & Human Behavior University of California Irvine
    University of California Irvine
    University of California Irvine
    University of California Irvine)

  • Wah Chiu

    (Stanford University
    Stanford University
    Stanford University)

Abstract

Huntington’s disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. While experiments with patient-derived induced pluripotent stem cells (iPSCs) can help understand disease, defining pathological biomarkers remains challenging. Here, we used cryogenic electron tomography to visualize neurites in HD patient iPSC-derived neurons with varying CAG repeats, and primary cortical neurons from BACHD, deltaN17-BACHD, and wild-type mice. In HD models, we discovered sheet aggregates in double membrane-bound organelles, and mitochondria with distorted cristae and enlarged granules, likely mitochondrial RNA granules. We used artificial intelligence to quantify mitochondrial granules, and proteomics experiments reveal differential protein content in isolated HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC- and BACHD neurons. We show that integrated ultrastructural and proteomic approaches may uncover early HD phenotypes to accelerate diagnostics and the development of targeted therapeutics for HD.

Suggested Citation

  • Gong-Her Wu & Charlene Smith-Geater & Jesús G. Galaz-Montoya & Yingli Gu & Sanket R. Gupte & Ranen Aviner & Patrick G. Mitchell & Joy Hsu & Ricardo Miramontes & Keona Q. Wang & Nicolette R. Geller & C, 2023. "CryoET reveals organelle phenotypes in huntington disease patient iPSC-derived and mouse primary neurons," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36096-w
    DOI: 10.1038/s41467-023-36096-w
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    References listed on IDEAS

    as
    1. Seda Koyuncu & Isabel Saez & Hyun Ju Lee & Ricardo Gutierrez-Garcia & Wojciech Pokrzywa & Azra Fatima & Thorsten Hoppe & David Vilchez, 2018. "The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington’s disease patients," Nature Communications, Nature, vol. 9(1), pages 1-22, December.
    2. Qiang Guo & Bin Huang & Jingdong Cheng & Manuel Seefelder & Tatjana Engler & Günter Pfeifer & Patrick Oeckl & Markus Otto & Franziska Moser & Melanie Maurer & Alexander Pautsch & Wolfgang Baumeister &, 2018. "The cryo-electron microscopy structure of huntingtin," Nature, Nature, vol. 555(7694), pages 117-120, March.
    3. Yvette C. Wong & Daniel Ysselstein & Dimitri Krainc, 2018. "Mitochondria–lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis," Nature, Nature, vol. 554(7692), pages 382-386, February.
    Full references (including those not matched with items on IDEAS)

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