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- EMDB-29081: CryoET tomogram of HD patient iPSC-derived neuron (Q66) with GRSF... -

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Basic information

Entry
Database: EMDB / ID: EMD-29081
TitleCryoET tomogram of HD patient iPSC-derived neuron (Q66) with GRSF1 KD treatment
Map dataRepresentative cryoET tomogram of neuron neurite differentiated from induced pluripotent stem cells derived from HD patient with a polyQ tract of length Q=66 with GRSF1 KD treatment
Sample
  • Cell: Human neuron differentiated from induced pluripotent stem cells derived from HD patient with a huntingtin gene containing a polyQ tract with 66 Qs with GRSF1 KD treatment
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 13, 2022-
Header (metadata) releaseFeb 22, 2023-
Map releaseFeb 22, 2023-
UpdateFeb 22, 2023-
Current statusFeb 22, 2023Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_29081.png

Downloads & links

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Map

FileDownload / File: emd_29081.map.gz / Format: CCP4 / Size: 1.5 GB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationRepresentative cryoET tomogram of neuron neurite differentiated from induced pluripotent stem cells derived from HD patient with a polyQ tract of length Q=66 with GRSF1 KD treatment
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
13.75 Å/pix.
x 280 pix.
= 3850.56 Å		13.75 Å/pix.
x 1440 pix.
= 19802.879 Å		13.75 Å/pix.
x 1023 pix.
= 14068.295 Å

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

generated in cubic-lattice coordinate

Voxel sizeX=Y=Z: 13.752 Å
Density

Histogram

Histogram (log scale)
Minimum - Maximum-3.0 - 3.0
Average (Standard dev.)0.004760497 (±0.9672907)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin-117209-209
Dimensions14401023280
Spacing10231440280
CellA: 14068.295 Å / B: 19802.879 Å / C: 3850.5596 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Human neuron differentiated from induced pluripotent stem cells d...

EntireName: Human neuron differentiated from induced pluripotent stem cells derived from HD patient with a huntingtin gene containing a polyQ tract with 66 Qs with GRSF1 KD treatment
Components
  • Cell: Human neuron differentiated from induced pluripotent stem cells derived from HD patient with a huntingtin gene containing a polyQ tract with 66 Qs with GRSF1 KD treatment

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Supramolecule #1: Human neuron differentiated from induced pluripotent stem cells d...

SupramoleculeName: Human neuron differentiated from induced pluripotent stem cells derived from HD patient with a huntingtin gene containing a polyQ tract with 66 Qs with GRSF1 KD treatment
type: cell / ID: 1 / Parent: 0 / Details: Mitochondria in situ
Source (natural)Organism: Homo sapiens (human) / Strain: CS02iHD66n4 / Organ: Skin / Tissue: Fibroblasts

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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
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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 5.0 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Final reconstructionNumber images used: 121

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