Kavli Affiliate: William Mobley
| Authors: Gong-Her Wu, Charlene Smith-Geater, Jesus G. Galaz-Montoya, Yingli Gu, Sanket R Gupte, Ranen Aviner, Patrick G. Mitchell, Joy Hsu, Ricardo Miramontes, Keona Q. Wang, Nicolette Geller, Cristina Danita, Lydia-Marie Joubert, Michael F. Schmid, Serena Yeung, Judith Frydman, William Mobley, Chengbiao Wu, Leslie M. Thompson and Wah Chiu
| Summary:
Huntington’s Disease (HD) is caused by an expanded CAG repeat in the huntingtin gene, yielding a Huntingtin protein with an expanded polyglutamine tract. Patient-derived induced pluripotent stem cells (iPSCs) can help understand disease; however, defining pathological biomarkers is 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 mitochondria with enlarged granules and distorted cristae, and thin sheet aggregates in double membrane-bound organelles. We used artificial intelligence to quantify mitochondrial granules, and proteomics to show differential protein content in HD mitochondria. Knockdown of Protein Inhibitor of Activated STAT1 ameliorated aberrant phenotypes in iPSC-neurons and reduced phenotypes in 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.