PXD066765-1

PXD066765 is an original dataset announced via ProteomeXchange.

Title	Caspase inhibition restores dopaminergic identity through the PKA–CREB–BDNF axis in Parkinson’s disease neurons
Description	The progressive loss of dopaminergic identity in midbrain neurons is a hallmark of Parkinson’s disease (PD), contributing to synaptic dysfunction and neurodegeneration. However, the molecular mechanisms linking disease-specific stress to dopaminergic transcriptional failure remain poorly understood. Here, we used human induced pluripotent stem cell (hiPSC)-derived midbrain dopaminergic neurons (mDAs) from sporadic PD patients to investigate early alterations in neuronal identity, plasticity, and survival. We found that PD-derived mDAs exhibit upregulation of phosphorylated α-synuclein, marked reductions in dopaminergic markers (TH, NURR1), deficient dopamine handling and impaired synaptogenesis. Transcriptomic and protein analyses revealed sustained activation of apoptotic caspases (caspase-3, -7) and downregulation of the PKA–CREB–BDNF signaling axis, which underpins dopaminergic differentiation and synaptic maturation. Pharmacological inhibition of caspases with Q-VD-OPh restored pCREB, BDNF, and downstream dopaminergic markers, leading to morphological recovery and functional synaptic rescue. Inhibition of PKA with H89 abrogated these effects, positioning the caspase–PKA–CREB cascade as a critical regulator of dopaminergic identity in PD neurons. These findings define a novel non-apoptotic role for caspases in disrupting the transcriptional program of mDAs and identify a druggable pathway capable of rescuing key aspects of dopaminergic function in a patient-derived cellular model. This work provides a mechanistic rationale for targeting caspase signaling in early-stage PD.
HostingRepository	PRIDE
AnnounceDate	2026-06-08
AnnouncementXML	Submission_2026-06-07_16:59:31.729.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Caterina Gabriele
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-07-30 07:24:39	ID requested
⏵ 1	2026-06-07 16:59:32	announced

Covello R, Benedetto GL, Scalise S, Gabriele C, Valente D, Zannino C, Puccio B, Quattrone A, Guzzi PH, Gaspari M, Quattrone A, Cuda G, Parrotta EI, Cytoskeletal Imbalance and Axonal Vulnerability in Sporadic PSP-RS: Early Changes in a Human iPSC-Derived Neuronal Model with Altered mTOR Signaling. Cells, 15(9):(2026) [pubmed]

10.3390/cells15090754;

submitter keyword: , synaptic function, Parkinson’s Disease, Midbrain dopaminergic neurons,Neurodegeneration, PKA-CREB pathway, Apoptosis, QVD-OPh

Giovanni Cuda
contact affiliation	Department of Experimental and Clinical Medicine, University of Catanzaro,Catanzaro (IT)
contact email	cuda@unicz.it
lab head
Caterina Gabriele
contact affiliation	Università Magna Graecia di Catanzaro
contact email	cgabriele86@gmail.com
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/2026/06/PXD066765

PRIDE project URI

• PRIDE
  1. PXD066765
     1. Label: PRIDE project
     2. Name: Caspase inhibition restores dopaminergic identity through the PKA–CREB–BDNF axis in Parkinson’s disease neurons