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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.
Afiliación
  • Wu GH; Department of Bioengineering, James H. Clark Center, Stanford University, Stanford, CA, 94305, USA.
  • Smith-Geater C; Department of Psychiatry & Human Behavior University of California Irvine, Irvine, CA, 92697, USA.
  • Galaz-Montoya JG; Department of Bioengineering, James H. Clark Center, Stanford University, Stanford, CA, 94305, USA.
  • Gu Y; Department of Neurosciences, University of California San Diego, La Jolla, CA, 92037-0662, USA.
  • Gupte SR; Department of Computer Science, Stanford University, Stanford, CA, 94305, USA.
  • Aviner R; Department of Biology, Stanford University, Stanford, CA, 94305, USA.
  • Mitchell PG; Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA, 94025, USA.
  • Hsu J; Department of Computer Science, Stanford University, Stanford, CA, 94305, USA.
  • Miramontes R; Department of Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, CA, 92697, USA.
  • Wang KQ; Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, 96267, USA.
  • Geller NR; Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, 96267, USA.
  • Hou C; Department of Bioengineering, James H. Clark Center, Stanford University, Stanford, CA, 94305, USA.
  • Danita C; Department of Bioengineering, James H. Clark Center, Stanford University, Stanford, CA, 94305, USA.
  • Joubert LM; Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA, 94025, USA.
  • Schmid MF; Division of CryoEM and Bioimaging, SSRL, SLAC National Accelerator Laboratory, Stanford University, Menlo Park, CA, 94025, USA.
  • Yeung S; Department of Computer Science, Stanford University, Stanford, CA, 94305, USA.
  • Frydman J; Department of Biomedical Data Science, Stanford University, Stanford, CA, 94305, USA.
  • Mobley W; Department of Biology, Stanford University, Stanford, CA, 94305, USA.
  • Wu C; Department of Genetics, Stanford University, Stanford, CA, 94305, USA.
  • Thompson LM; Department of Neurosciences, University of California San Diego, La Jolla, CA, 92037-0662, USA.
  • Chiu W; Department of Neurosciences, University of California San Diego, La Jolla, CA, 92037-0662, USA.
Nat Commun ; 14(1): 692, 2023 02 08.
Article en En | MEDLINE | ID: mdl-36754966
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Huntington / Células Madre Pluripotentes Inducidas Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Enfermedad de Huntington / Células Madre Pluripotentes Inducidas Límite: Animals / Humans Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido