PXD051032-1

PXD051032 is an original dataset announced via ProteomeXchange.

Title	Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function
Description	Loss of function of the enzyme succinic semialdehyde dehydrogenase (SSADH) impairs metabolism of the inhibitory neurotransmitter GABA. This neurometabolic disorder, known as SSADH deficiency, leads to great neurochemical imbalances and severe neurological symptoms, including cognitive deficits and seizures. Despite the known identity of the enzymatic deficit, the underlying pathology of SSADH deficiency remain unclear. To uncover new mechanisms of the disease, we here provide an integrative analysis of cerebral protein expression, functional metabolism and lipid composition in a genetic mouse model of SSADH deficiency (ALDH5A1 knock-out mice). Our proteomic analysis revealed a clear regional vulnerability, as protein alterations primarily manifested in the hippocampus and cerebral cortex of the ALDH5A1 knock-out mice. These regions displayed aberrant expression of multiple proteins linked to amino acid homeostasis, mitochondria, glial function and myelination. Stable isotope tracing in acutely isolated brain slices demonstrated an overall maintained oxidative metabolism of glucose, but a selective decrease in astrocyte metabolic activity in the cerebral cortex of ALDH5A1 knock-out mice. In contrast, an elevated capacity of oxidative glutamine metabolism was observed in the ALDH5A1 knock-out mice, which may serve as a metabolic compensation of impaired astrocyte glutamine synthesis. In addition to reduced expression of critical oligodendrocyte proteins, a severe depletion of myelin-enriched sphingolipids was found in the ALDH5A1 knock-out brain, suggesting dysregulation or degeneration of myelin. Our study highlight that impaired astrocyte and oligodendrocyte function may play crucial roles in SSADH deficiency pathology, strongly warranting an exploration of the therapeutic potential of these cells.
HostingRepository	PRIDE
AnnounceDate	2024-06-26
AnnouncementXML	Submission_2024-06-26_09:30:25.787.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Niels Henning Skotte
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	timsTOF Pro

Revision	Datetime	Status	ChangeLog Entry
0	2024-03-27 19:55:54	ID requested
⏵ 1	2024-06-26 09:30:26	announced
2	2024-10-22 06:47:31	announced	2024-10-22: Updated project metadata.

10.1002/GLIA.24585;

submitter keyword: SSADH deficiency, brain energy metabolism, glutamate/GABA-glutamine cycle, myelin, Proteomics, glia

Niels Henning Skotte
contact affiliation	Department for Drug Design and Pharmacology, University of Copenhagen
contact email	Niels.Skotte@sund.ku.dk
lab head
Niels Henning Skotte
contact affiliation	University of Copenhagen
contact email	niels.skotte@sund.ku.dk
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD051032
     1. Label: PRIDE project
     2. Name: Deficient brain GABA metabolism leads to widespread impairments of astrocyte and oligodendrocyte function