PXD038399

PXD038399 is an original dataset announced via ProteomeXchange.

Title	Alterations in SHH signal transduction introduce a state of hypometabolism in sporadic Parkinson's disease
Description	Sporadic Parkinson’s Disease (sPD) is a progressive neurodegenerative disorder caused by a combination of genetic and environmental factors, however, the etiology remains largely elusive. Here, we used human iPSCs from late onset sPD patients, which were cultivated in vitro for up to 60 passages and screened for known PD associated alterations. Following long-term in vitro cultivation, exclusively neural cells derived from sPD patients developed a reduced mitochondrial respiration and glucose consumption reflecting a sPD specific state of hypometabolism. Integrated analysis of transcriptome, proteome and non-targeted metabolome data identified the citric acid cycle as being the bottleneck in sPD metabolism. A 13C metabolic flux analysis further unraveled the α-ketoglutarate dehydrogenase complex as being central for a reduced flux through the citric acid cycle. This resulted in a substrate availability problem for the electron transport chain and thus a reduced mitochondrial ATP production. Notably, this alterations in basal cellular metabolism were introduced by altered SHH signal transduction due to dysfunctional primary cilia. Upon inhibiting the enhanced SHH signal transduction in sPD, glucose uptake and the activity of the α-ketoglutarate dehydrogenase complex could be restored. Thus, inhibiting overactive SHH signaling maybe a potential neuroprotective therapy for sPD.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:05:01.732.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Mario Oroshi
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-26 04:11:46	ID requested
1	2023-10-05 08:18:52	announced
⏵ 2	2024-10-22 06:05:02	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Mass Spectrometry, Neuronal Precursor cell,Parkinson's Disease, Proteomics

Matthias Mann
contact affiliation	Max Planck Institute of Biochemistry
contact email	mmann@biochem.mpg.de
lab head
Mario Oroshi
contact affiliation	Proteomics
contact email	oroshi@biochem.mpg.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038399
     1. Label: PRIDE project
     2. Name: Alterations in SHH signal transduction introduce a state of hypometabolism in sporadic Parkinson's disease