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- EMDB-29210: CryoET tomogram of purified mitochondria from HD patient iPSC-der... -

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Basic information

Entry
Database: EMDB / ID: EMD-29210
TitleCryoET tomogram of purified mitochondria from HD patient iPSC-derived neuron (Q109)
Map dataRepresentative IMOD-reconstructed cryoET tomogram of mitochondria purified from neuron differentiated from induced pluripotent stem cells derived from HD patient with a polyQ tract of length Q=109
Sample
  • Cell: Purified mitochondria from human neuron differentiated from induced pluripotent stem cells derived from HD patient with a huntingtin gene containing a polyQ tract with 109 Qs
Biological speciesHomo sapiens (human)
Methodelectron tomography / cryo EM
AuthorsWu GH / Smith-Geater C / Galaz-Montoya JG / Mitchell PG / Thompson LM / Chiu W
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)P01NS092525 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)S10OD021600 United States
National Institutes of Health/National Institute on Aging (NIH/NIA)R35NS116872 United States
CitationJournal: Nat Commun / Year: 2023
Title: CryoET reveals organelle phenotypes in huntington disease patient iPSC-derived and mouse primary neurons.
Authors: 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 ...Authors: 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 / Wah Chiu /
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 ...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.
History
DepositionDec 16, 2022-
Header (metadata) releaseMar 1, 2023-
Map releaseMar 1, 2023-
UpdateMar 1, 2023-
Current statusMar 1, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29210.png

Downloads & links

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Map

FileDownload / File: emd_29210.map.gz / Format: CCP4 / Size: 1 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationRepresentative IMOD-reconstructed cryoET tomogram of mitochondria purified from neuron differentiated from induced pluripotent stem cells derived from HD patient with a polyQ tract of length Q=109
Voxel sizeX=Y=Z: 14 Å
Density
Minimum - Maximum-36.189182 - 34.233932
Average (Standard dev.)3.9955648e-09 (±1.0)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-512-512-128
Dimensions10241024256
Spacing10241024256
CellA: 14335.999 Å / B: 14335.999 Å / C: 3583.9998 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Purified mitochondria from human neuron differentiated from induc...

EntireName: Purified mitochondria from human neuron differentiated from induced pluripotent stem cells derived from HD patient with a huntingtin gene containing a polyQ tract with 109 Qs
Components
  • Cell: Purified mitochondria from human neuron differentiated from induced pluripotent stem cells derived from HD patient with a huntingtin gene containing a polyQ tract with 109 Qs

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Supramolecule #1: Purified mitochondria from human neuron differentiated from induc...

SupramoleculeName: Purified mitochondria from human neuron differentiated from induced pluripotent stem cells derived from HD patient with a huntingtin gene containing a polyQ tract with 109 Qs
type: cell / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human) / Organ: Skin / Tissue: Fibroblast / Cell: CS09iHD109n1

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Experimental details

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Structure determination

Methodcryo EM
Processingelectron tomography
Aggregation statecell

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Sample preparation

BufferpH: 7
VitrificationCryogen name: ETHANE
SectioningOther: NO SECTIONING
Fiducial markerManufacturer: Fisher Scientific / Diameter: 15 nm

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Electron microscopy

MicroscopeTFS KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 5.0 µm / Nominal defocus min: 5.0 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Detector mode: COUNTING / Number real images: 121 / Average electron dose: 1.01 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionNumber images used: 121

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