<<< Full experiment listing

PXD036797

PXD036797 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleS-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons
DescriptionA causal relationship between mitochondrial metabolic dysfunction and neurodegeneration has been strongly implicated in synucleinopathies, including Parkinson’s disease (PD) and Lewy body dementia (LBD), but the underlying molecular basis is not fully understood. Here, using human induced pluripotent stem cell (hiPSC)-derived neurons bearing a pathological point mutation in the gene encoding α-synuclein (αSyn) protein, we report that the presence of many aberrantly S-nitrosylated proteins, including multiple tricarboxylic acid (TCA) cycle enzymes, which results in inhibition of their activity, as assessed by carbon-labeled metabolic flux experiments. The block in the TCA cycle principally affects the step at -ketoglutarate dehydrogenase/succinyl coenzyme-A synthetase, metabolizing -ketoglutarate to succinate. Notably, human LBD brain manifests a similar pattern of aberrantly S-nitrosylated TCA enzymes, indicating the pathophysiological relevance of these results. Inhibition of mitochondrial energy metabolism in neurons is known to compromise dendritic length and synaptic integrity, eventually leading to neuronal cell death, with consequent neurodegenerative phenotypes. Our new evidence indicates that redox-mediated inhibition of the TCA cycle via aberrant protein S-nitrosylation contributes to this bioenergetic failure.
HostingRepositoryPRIDE
AnnounceDate2024-10-17
AnnouncementXMLSubmission_2024-10-17_02:39:49.966.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterHossein Fazelinia
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListdihydroxylated residue; monohydroxylated residue
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02022-09-17 02:55:03ID requested
12024-10-17 02:39:50announced
Publication List
10.1016/j.chembiol.2023.06.018;
Doulias PT, Yang H, Andreyev AY, Dolatabadi N, Scott H, K Raspur C, Patel PR, Nakamura T, Tannenbaum SR, Ischiropoulos H, Lipton SA, S-Nitrosylation-mediated dysfunction of TCA cycle enzymes in synucleinopathy studied in postmortem human brains and hiPSC-derived neurons. Cell Chem Biol, 30(8):965-975.e6(2023) [pubmed]
Keyword List
submitter keyword: S-Nitrosylation, alpha-synuclein, TCA cycle, mitochondrial dysfunction
Contact List
Harry Ischiropoulos, Ph.D.
contact affiliationChildren's Hospital of Philadelphia 416B Abramson Pediatric Research Center Philadelphia, PA 19104 Office: 215-590-5320 Lab: 215-590-5319
contact emailischirop@pennmedicine.upenn.edu
lab head
Hossein Fazelinia
contact affiliationChildren's Hospital of Philadelphia
contact emailfazeliniah@email.chop.edu
dataset submitter
Full Dataset Link List
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/2024/10/PXD036797
PRIDE project URI
Repository Record List
[ + ]