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PXD042436

PXD042436 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleMetabolic bypass partially rescues S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer’s disease human neurons
DescriptionIn 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.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_06:42:31.546.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterHossein Fazelinia
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumentQ Exactive HF
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-05-23 07:32:23ID requested
12024-05-24 02:08:48announced
22024-10-22 06:42:37announced2024-10-22: Updated project metadata.
Publication List
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]
Keyword List
submitter keyword: S-nitrosylation,Alzheimer’s disease, mitochondrial metabolism, TCA cycle inhibition
Contact List
Stuart A. Lipton
contact affiliationDepartment of Molecular Medicine and Neurodegeneration New Medicines Center, The Scripps Research Institute, La Jolla, CA 92037, USA
contact emailslipton@scripps.edu
lab head
Hossein Fazelinia
contact affiliationChildren's Hospital of Philadelphia
contact emailfazeliniah@email.chop.edu
dataset submitter
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Dataset FTP location
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