PXD063729

PXD063729 is an original dataset announced via ProteomeXchange.

Title	SNCA triplication disrupts proteostasis and extracellular architecture prior to neurodegeneration in human midbrain organoids
Description	Synucleinopathies, including Parkinson’s disease, are characterized by α-synuclein aggregation and progressive neurodegeneration, yet the early molecular events linking SNCA gene dosage to disrupted proteostasis remain poorly understood. Here, we used human midbrain organoids carrying an SNCA triplication (SNCA Trip) and the isogenic corrected line (SNCA Isog) to dissect early pathogenic mechanisms in a 3D human model of synucleinopathy. We combined immunohistochemistry, immunoblotting, tandem mass tag proteomics, bulk RNA sequencing, and ribosome profiling to systematically characterize molecular alterations in SNCA Trip organoids at day 50 (D50) and day 100 (D100) of maturation. SNCA Trip organoids exhibited increased α-synuclein accumulation, neuromelanin deposition, and activation of mTORC1 (p-rpS6), ERK1/2, and p-eIF2α signalling pathways by D100. Proteomic and transcriptomic analyses revealed upregulation of cytoskeletal, synaptic, and axonal development pathways, alongside significant downregulation of extracellular matrix (ECM) components. Ribosome profiling showed minimal global translational changes but uncovered selective translational buffering of neuronal and ECM-associated transcripts. Confocal imaging confirmed progressive disorganization of pericellular and interstitial ECM structures around neurons in SNCA Trip organoids. Our findings demonstrate that SNCA triplication induces early proteostatic disruption and extracellular matrix remodelling prior to neurodegeneration, suggesting that altered translation and ECM homeostasis may contribute to disease initiation and progression. Targeting these early aberrant mechanisms may offer new therapeutic opportunities for synucleinopathies, such as Parkinson’s Disease.
HostingRepository	PRIDE
AnnounceDate	2026-04-06
AnnouncementXML	Submission_2026-04-05_16:27:37.346.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Frank Stein
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2025-05-07 08:08:55	ID requested
⏵ 1	2026-04-05 16:27:38	announced

Statoulla E, Zafeiri M, Chalkiadaki K, Voudouri G, Gkika KS, Papazoglou C, Durcan TM, Khoutorsky A, Jafarnejad SM, Maguire S, Dityatev A, Gkogkas CG, SNCA triplication disrupts proteostasis and extracellular architecture prior to neurodegeneration in human midbrain organoids. NPJ Parkinsons Dis, 12(1):(2026) [pubmed]

10.1038/s41531-026-01292-0;

submitter keyword: translational control, Parkinson's Disease (PD),SNCA

Christos G. Gkogkas
contact affiliation	Biomedical Research Institute, Foundation for Research and Technology-Hellas, Ioannina, Greece.
contact email	cgkogkas@bri.forth.gr
lab head
Frank Stein
contact affiliation	EMBL
contact email	frank.stein@embl.de
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2026/04/PXD063729

PRIDE project URI

• PRIDE
  1. PXD063729
     1. Label: PRIDE project
     2. Name: SNCA triplication disrupts proteostasis and extracellular architecture prior to neurodegeneration in human midbrain organoids