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- EMDB-46764: Mitochondrial membrane with external amorphous alpha-synuclein ag... -

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Basic information

Entry
Database: EMDB / ID: EMD-46764
TitleMitochondrial membrane with external amorphous alpha-synuclein aggregate
Map dataMitochondrial membrane with external amorphous alpha-synuclein aggregate
Sample
  • Organelle or cellular component: Cell lysate from 3k M17D neuroblastoma cell line
Keywordsintrinsic disorder / aggregate / amorphous / phase separation / neurodegeneration / membrane binding / neurotransmitter regulation / EXOCYTOSIS
Biological speciesHomo sapiens (human)
Methodelectron tomography / cryo EM
AuthorsJaber N / Dai W
Funding support United States, France, 2 items
OrganizationGrant numberCountry
National Science Foundation (NSF, United States)MCB-2046180 United States
Human Frontier Science Program (HFSP)LT001044/2017 France
CitationJournal: Cell Rep / Year: 2025
Title: Increased burden of rare risk variants across gene expression networks predisposes to sporadic Parkinson's disease.
Authors: Elena Eubanks / Katelyn VanderSleen / Jiya Mody / Neha Patel / Benjamin Sacks / Mahsa Darestani Farahani / Jinying Wang / Jordan Elliott / Nora Jaber / Fulya Akçimen / Sara Bandres-Ciga / ...Authors: Elena Eubanks / Katelyn VanderSleen / Jiya Mody / Neha Patel / Benjamin Sacks / Mahsa Darestani Farahani / Jinying Wang / Jordan Elliott / Nora Jaber / Fulya Akçimen / Sara Bandres-Ciga / Fadel Helweh / Jun Liu / Sanjana Archakam / Robert Kimelman / Bineet Sharma / Philip Socha / Ananya Guntur / Yiming Huang / Nagendran Ramalingam / Elyse Guadagno / Tim Bartels / Ulf Dettmer / M Maral Mouradian / Amir Houshang Bahrami / Wei Dai / Jean Baum / Zheng Shi / John Hardy / Eleanna Kara /
Abstract: Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson's disease (PD). Through a high-throughput screen, we recently identified 38 ...Alpha-synuclein (αSyn) is an intrinsically disordered protein that accumulates in the brains of patients with Parkinson's disease (PD). Through a high-throughput screen, we recently identified 38 genes whose knockdown modulates αSyn propagation. Here, we show that, among those, TAX1BP1 regulates how αSyn interacts with lipids, and ADAMTS19 modulates how αSyn phase separates into inclusions, adding to the growing body of evidence implicating those processes in PD. Through RNA sequencing, we identify several genes that are differentially expressed after knockdown of TAX1BP1 or ADAMTS19 and carry an increased frequency of rare risk variants in patients with PD versus healthy controls. Those differentially expressed genes cluster within modules in regions of the brain that develop high degrees of αSyn pathology. We propose a model for the genetic architecture of sporadic PD: increased burden of risk variants across genetic networks dysregulates pathways underlying αSyn homeostasis and leads to pathology and neurodegeneration.
History
DepositionAug 27, 2024-
Header (metadata) releaseMar 5, 2025-
Map releaseMar 5, 2025-
UpdateMay 14, 2025-
Current statusMay 14, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_46764.png

Downloads & links

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Map

FileDownload / File: emd_46764.map.gz / Format: CCP4 / Size: 949.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationMitochondrial membrane with external amorphous alpha-synuclein aggregate
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
17.2 Å/pix.
x 280 pix.
= 4816. Å		17.2 Å/pix.
x 959 pix.
= 16494.801 Å		17.2 Å/pix.
x 927 pix.
= 15944.4 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: 17.2 Å
Density

Histogram

Histogram (log scale)
Minimum - Maximum-13447.274999999999636 - 7667.854500000000371
Average (Standard dev.)94.930539999999993 (±385.169460000000015)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin16-16140
Dimensions959927280
Spacing927959280
CellA: 15944.4 Å / B: 16494.8 Å / C: 4816.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Cell lysate from 3k M17D neuroblastoma cell line

EntireName: Cell lysate from 3k M17D neuroblastoma cell line
Components
  • Organelle or cellular component: Cell lysate from 3k M17D neuroblastoma cell line

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Supramolecule #1: Cell lysate from 3k M17D neuroblastoma cell line

SupramoleculeName: Cell lysate from 3k M17D neuroblastoma cell line / type: organelle_or_cellular_component / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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: 7.4
Component:
ConcentrationFormulaName
20.0 mMTris-BaseTris-Base
10.0 mMNaClsodium chloride
3.0 mMMgCl2magnesium chloride
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 293.15 K / Instrument: LEICA EM GP / Details: Blot time: 6 seconds.
SectioningOther: NO SECTIONING
Fiducial markerManufacturer: EMS / Diameter: 6 nm

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 20 eV
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k x 4k) / Detector mode: COUNTING / Number real images: 41 / Average electron dose: 1.5 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 10.0 µm / Nominal defocus min: 8.0 µm / Nominal magnification: 31000
Sample stageCooling holder cryogen: NITROGEN
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Final reconstructionSoftware - Name: IMOD / Number images used: 41
CTF correctionType: NONE

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