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

• Published in: Nature communications Vol. 14; no. 1; p. 692
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.02.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 101/28; 631/378/1689/1558; 631/535/1258/1260; Animal models; Animals; Artificial Intelligence; Axons; BASIC BIOLOGICAL SCIENCES; Biomarkers; Cristae; Cryoelectron tomography; Cytology; Disease Models, Animal; Drug development; Granular materials; Humanities and Social Sciences; Humans; Huntingtin; Huntingtin Protein - genetics; Huntingtin Protein - metabolism; Huntington Disease - metabolism; Huntington's disease; Huntingtons disease; Induced Pluripotent Stem Cells - metabolism; Inhibitory postsynaptic potentials; Mice; Mitochondria; Mitochondria - metabolism; multidisciplinary; Mutation; Neurodegenerative diseases; Neurons; Neurons - metabolism; Organelles; Phenotype; Phenotypes; Pluripotency; Polyglutamine; Proteins; Proteomics; Science; Science (multidisciplinary); Stat1 protein; Stem cell transplantation; Stem cells; Tomography; Trinucleotide repeat diseases; Trinucleotide repeats
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-36096-w

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. Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a genetic mutation in the huntingtin gene (HTT). Here, cryo electron tomography provides insights into the morphology of the cells derived from patients with HD and mouse models of the disease.