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

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, Cathy Hou, Cristina Danita, Lydia-Marie Joubert, Michael F. Schmid, Serena Yeung, Judith Frydman, William Mobley, Chengbiao Wu, Leslie M. Thompson () and Wah Chiu ()
Additional contact information
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
Judith Frydman: 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
Wah Chiu: Stanford University

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36096-w

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