PXD042436

PXD042436 is an original dataset announced via ProteomeXchange.

Title	Metabolic bypass partially rescues S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer’s disease human neurons
Description	In Alzheimer’s disease (AD), dysfunctional mitochondrial metabolism has been associated with synaptic loss, the major pathological correlate of cognitive decline. Mechanistic insight for this relationship, however, is still lacking. Here, comparing isogenic wild-type and AD mutant human induced pluripotent stem cell (hiPSC)-derived cerebrocortical neurons (hiN), we found evidence for compromised mitochondrial energy production in AD using the Seahorse platform to analyze glycolysis and oxidative phosphorylation (OXPHOS). By isotope-labeled metabolic flux experiments, a major block in activity occurred in the tricarboxylic acid (TCA) cycle at the -ketoglutarate dehydrogenase (KGDH)/succinyl coenzyme-A synthetase step, metabolizing -ketoglutarate to succinate. Associated with this block we found aberrant protein S-nitrosylation of KGDH subunits that are known to inhibit enzyme function. This aberrant S-nitrosylation was documented not only in AD-hiN but also in postmortem human AD brains vs. controls, as assessed by two separate unbiased mass spectrometry platforms using both SNOTRAP identification of S-nitrosothiols and chemoselective-enrichment of S-nitrosoproteins. Treatment with dimethyl succinate a cell-permeable derivative of a TCA substrate downstream to the block resulted in partial rescue of mitochondrial bioenergetic function as well as improvement in synapse number in AD-hiN. Our findings have therapeutic implications as proof-of-principle that rescue of mitochondrial energy metabolism can ameliorate synaptic loss in hiPSC-based models of AD.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:42:31.546.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Hossein Fazelinia
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-23 07:32:23	ID requested
1	2024-05-24 02:08:48	announced
⏵ 2	2024-10-22 06:42:37	announced	2024-10-22: Updated project metadata.

10.1002/advs.202306469;

Andreyev AY, Yang H, Doulias PT, Dolatabadi N, Zhang X, Luevanos M, Blanco M, Baal C, Putra I, Nakamura T, Ischiropoulos H, Tannenbaum SR, Lipton SA, Metabolic Bypass Rescues Aberrant S-nitrosylation-Induced TCA Cycle Inhibition and Synapse Loss in Alzheimer's Disease Human Neurons. Adv Sci (Weinh), 11(12):e2306469(2024) [pubmed]

submitter keyword: S-nitrosylation,Alzheimer’s disease, mitochondrial metabolism, TCA cycle inhibition

Stuart A. Lipton
contact affiliation	Department of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037, USA
contact email	slipton@scripps.edu
lab head
Hossein Fazelinia
contact affiliation	Children's Hospital of Philadelphia
contact email	fazeliniah@email.chop.edu
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/2024/05/PXD042436

PRIDE project URI

• PRIDE
  1. PXD042436
     1. Label: PRIDE project
     2. Name: Metabolic bypass partially rescues S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer’s disease human neurons