PXD056511

PXD056511 is an original dataset announced via ProteomeXchange.

Title	USP14 inhibition enhances Parkin-independent mitophagy in iNeurons
Description	Loss of proteostasis is well documented during physiological aging and depends on the progressive decline in the activity of two major degradative mechanisms: the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway. This decline in proteostasis is exacerbated in age-associated neurodegenerative diseases, such as Parkinson’s Disease (PD). In PD, patients develop an accumulation of aggregated proteins and dysfunctional mitochondria, which leads to ROS production, neuroinflammation and neurodegeneration. We recently reported that inhibition of the deubiquitinating enzyme USP14, which is known to enhance both the UPS and autophagy, increases lifespan and rescues the pathological phenotype of two Drosophila models of PD. Studies on the effects of USP14 inhibition in mammalian neurons have not yet been conducted. To close this gap, we exploited iNeurons differentiated from human embryonic stem cells (hESCs), and investigated the effect of inhibiting USP14 in these cultured neurons. Quantitative global proteomics analysis performed following genetic ablation or pharmacological inhibition of USP14 demonstrated that USP14 loss of function specifically promotes mitochondrial autophagy in iNeurons. Biochemical and imaging data also showed that USP14 inhibition enhances mitophagy. The mitophagic effect of USP14 inhibition proved to be PINK1/Parkin- independent, instead relying on expression of the mitochondrial E3 Ubiquitin Ligase MITOL/MARCH5. Notably, USP14 inhibition normalized the mitochondrial defects of Parkin KO human neurons.
HostingRepository	PRIDE
AnnounceDate	2024-12-18
AnnouncementXML	Submission_2024-12-18_15:50:34.855.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD056511
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Miguel Prado
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2024-10-04 11:43:08	ID requested
⏵ 1	2024-12-18 15:50:35	announced

Bernardo G, Prado MA, Dashtmian AR, Favaro M, Mauri S, Borsetto A, Marchesan E, Paulo JA, Gygi SP, Finley DJ, Ziviani E, USP14 inhibition enhances Parkin-independent mitophagy in iNeurons. Pharmacol Res, 210():107484(2024) [pubmed]

10.6019/PXD056511;

10.1016/j.phrs.2024.107484;

submitter keyword: USP14, Mitophagy, Autophagy, UPS, Parkin, MARCH5/MITOL, PINK1

Miguel Prado
contact affiliation	Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
contact email	miguel.prado@ispasturias.es
lab head
Miguel Prado
contact affiliation	Harvard Medical School, Boston, USA Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain (lab head)
contact email	miguel.prado@ispasturias.es
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD056511
     1. Label: PRIDE project
     2. Name: USP14 inhibition enhances Parkin-independent mitophagy in iNeurons