PXD042436 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
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. |
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 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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD042436
- Label: PRIDE project
- Name: Metabolic bypass partially rescues S-nitrosylation-induced TCA cycle inhibition and synapse loss in Alzheimer’s disease human neurons