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

Wu, Gong-Her; Smith-Geater, Charlene; Galaz-Montoya, Jesús G.; Gu, Yingli; Gupte, Sanket R.; Aviner, Ranen; Mitchell, Patrick G.; Hsu, Joy; Miramontes, Ricardo; Wang, Keona Q.; Geller, Nicolette R.; Hou, Cathy; Danita, Cristina; Joubert, Lydia-Marie; Schmid, Michael F.; Yeung, Serena; Frydman, Judith; Mobley, William; Wu, Chengbiao; Thompson, Leslie M.; Chiu, Wah

doi:10.1038/s41467-023-36096-w

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

Journal Article · Wed Feb 08 04:00:00 EST 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-36096-w· OSTI ID:2004997

Wu, Gong-Her ^[1]; ^[2]; Galaz-Montoya, Jesús G. ^[3]; ^[4]; Gupte, Sanket R. ^[3]; Aviner, Ranen ^[3]; ^[5]; ^[3]; Miramontes, Ricardo ^[2]; ^[2]; Geller, Nicolette R. ^[2]; Hou, Cathy ^[3]; Danita, Cristina ^[3]; ^[5]; ^[5]; ^[3]; ^[3]; Mobley, William ^[4]; Wu, Chengbiao ^[4]; ^[2] more »

Stanford University, CA (United States); SLAC
University of California, Irvine, CA (United States)
Stanford University, CA (United States)
University of California San Diego, La Jolla, CA (United States)
Stanford University, CA (United States); SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)

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.

View Accepted Manuscript (DOE)

Research Organization:: SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH)

Grant/Contract Number:: AC02-76SF00515

OSTI ID:: 2004997

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 14; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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Plunge Freezing: A Tool for the Ultrastructural and Immunolocalization Studies of Suspension Cells in Transmission Electron Microscopy Blancard, Corinne; Salin, Bénédicte Journal of Visualized Experiments, Issue 123 https://doi.org/10.3791/54874	journal	May 2017
Mitochondrial protein import regulates cytosolic protein homeostasis and neuronal integrity Liu, Wei; Duan, Xiuying; Fang, Xuefei Taylor & Francis https://doi.org/10.6084/m9.figshare.6571382	dataset	January 2018
Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons Nekrasov, Evgeny; Vigont, Vladimir; Klyushnikov, Sergey Figshare https://doi.org/10.6084/m9.figshare.c.3634712.v1	collection	January 2016
Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease Zhou, Ya; Peskett, Thomas R.; Landles, Christian figshare https://doi.org/10.6084/m9.figshare.c.5389167.v1	collection	January 2021
TRiC’s tricks inhibit huntingtin aggregation Shahmoradian, Sarah H.; Galaz-Montoya, Jesus G.; Schmid, Michael F. eLife, Vol. 2 https://doi.org/10.7554/eLife.00710	journal	July 2013
Control of the structural landscape and neuronal proteotoxicity of mutant Huntingtin by domains flanking the polyQ tract Shen, Koning; Calamini, Barbara; Fauerbach, Jonathan A. eLife, Vol. 5 https://doi.org/10.7554/eLife.18065	journal	October 2016

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