PXD006647

PXD006647 is an original dataset announced via ProteomeXchange.

Title	SQSTM1/p62-directed metabolic reprogramming is essential for normal neurodifferentiation
Description	Neurodegenerative disorders are an increasingly common and irreversible burden on society, often affecting the ageing population, but their aetiology and disease mechanisms are poorly understood. Studying monogenic neurodegenerative diseases, with known genetic cause, provides an opportunity to understand cellular mechanisms also affected in more complex disorders. We recently reported that loss-of-function mutations in the autophagy adaptor protein, SQSTM1/p62, lead to a slowly progressive neurodegenerative disease presenting in childhood. To further elucidate the neuronal involvement, we studied the cellular consequences of loss of p62 in a neuroepithelial stem (NES) cell model and differentiated neurones, derived from reprogrammed p62 patient cells, or by CRISPR/Cas9-directed gene editing in NES cells. Transcriptomic and proteomic analyses suggest that p62 is essential for neuronal differentiation by controlling the metabolic shift from aerobic glycolysis to oxidative phosphorylation required for neuronal maturation. This shift is blocked by the failure to sufficiently downregulate lactate dehydrogenase expression due to the loss of p62, possibly through impaired Hif-1α downregulation and increased sensitivity to oxidative stress. The findings implicate an important role for p62 in neuronal energy metabolism and particularly in the regulation of the shift between glycolysis and oxidative phosphorylation, required for normal neurodifferentiation.
HostingRepository	PRIDE
AnnounceDate	2019-03-05
AnnouncementXML	Submission_2019-03-05_04:19:57.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Florian Schober
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2017-06-01 08:34:44	ID requested
1	2019-03-05 03:06:20	announced
⏵ 2	2019-03-05 04:19:58	announced	Updated publication reference for PubMed record(s): 30827875.

Calvo-Garrido J, Maffezzini C, Schober FA, Clemente P, Uhlin E, Kele M, Stranneheim H, Lesko N, Bruhn H, Svenningsson P, Falk A, Wedell A, Freyer C, Wredenberg A, SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation. Stem Cell Reports, 12(4):696-711(2019) [pubmed]

curator keyword: Biomedical

submitter keyword: SQSTM1, p62, hypoxia, mitochondria, neurodifferentiation, neuroepithelial-like stem cells, neuronal development, oxidative stress, mitophagy

Anna Wredenberg
contact affiliation	Division of Molecular Metabolism, Karolinska Institute, Retziusväg 8, 171 77 Stockholm, Sweden
contact email	anna.wredenberg@ki.se
lab head
Florian Schober
contact affiliation	MMK, Karolinska Institute
contact email	florian.schober@ki.se
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/2019/03/PXD006647

PRIDE project URI

• PRIDE
  1. PXD006647
     1. Label: PRIDE project
     2. Name: SQSTM1/p62-directed metabolic reprogramming is essential for normal neurodifferentiation