PXD053147

PXD053147 is an original dataset announced via ProteomeXchange.

Title	PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson’s disease to perinatal lethality and disrupt mitochondrial pathways
Description	Dissecting biopathways unveiled by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson’s disease (PD) and neurodegeneration, hence catalyzing the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and human neurodegeneration. We found that biallelic PSMF1 missense and loss-of-function variants cosegregate with phenotypes from early-onset PD and parkinsonism to perinatal lethal neurodegeneration across 15 unrelated pedigrees with 22 affected subjects, showing clear-cut genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/PI31, a highly conserved, ubiquitously expressed partner of the 20S proteasome and neurodegeneration-associated F-box-O 7 and valosin-containing proteins. We demonstrate that PSMF1 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila and conditional knockout mouse exhibiting age-dependent motor impairment, with diffuse gliosis in mice. These findings unequivocally link defective PSMF1 to early-onset PD and neurodegeneration and suggest that mitochondrial dysfunction contributes to neuronal loss.
HostingRepository	PRIDE
AnnounceDate	2026-03-03
AnnouncementXML	Submission_2026-03-03_11:25:48.422.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Matthew Jaconelli
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Astral

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-16 09:07:40	ID requested
⏵ 1	2026-03-03 11:25:49	announced

10.1101/2024.06.19.24308302;

Magrinelli F, Tesson C, Angelova PR, Rodriguez JA, Scardamaglia A, O'Callaghan B, Lowe SA, Salazar-Villacorta A, Chung BH, Jaconelli M, Vona B, Esteras N, Mammana A, Shimazu J, Kwong AK, Courtin T, Alavi S, Maroofian R, Nirujogi R, Severino M, Monfrini E, Rocca C, Lewis PA, Efthymiou S, Buchert R, Sofan L, Lis P, Pinon C, Breedveld GJ, Chui MM, Murphy D, Pitz V, Makarious MB, Baiardi S, Volin M, Cassar M, Hassan BA, Iftikhar S, Bauer P, Tinazzi M, Svetel M, Samanci B, Hana, ğ, as, ı HA, Bilgi, ç B, Cavallieri F, Santangelo M, Obeso JA, Kurtis MM, Cogan G, Kiziltan G, G, ü, l-Demirkale T, Tireli H, Y, ü, ksel GA, Yal, ç, ı, n-Cakmakli G, Elibol B, Bari, š, i, ć N, Ng EW, Fan SS, Hershkovitz T, Weiss K, Alvi JR, Sultan T, Alkhawaja IA, Froukh T, Alrukban HAE, Fauth C, Schatz UA, Z, ö, ggeler T, Zech M, Stals K, Varghese V, Gandhi S, Blauwendraat C, Hardy JA, Di Fonzo A, Bonifati V, Haack TB, Bertoli-Avella AM, Lesage S, Ba, ş, ak AN, Steinfeld R, Parchi P, Jepson JEC, Alessi DR, Brice A, Steller H, Abramov AY, Bhatia KP, Houlden H, Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality and disrupt mitochondrial function. medRxiv, ():(2025) [pubmed]

submitter keyword: Parkinson's disease,PSMF1, neurodegeneration

Prof. Dario
contact affiliation	Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee; Dow Street, Dundee DD1 5EH, U.K.
contact email	d.r.alessi@dundee.ac.uk
lab head
Matthew Jaconelli
contact affiliation	University of Dundee
contact email	mjaconelli001@dundee.ac.uk
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/2026/03/PXD053147

PRIDE project URI

• PRIDE
  1. PXD053147
     1. Label: PRIDE project
     2. Name: PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson’s disease to perinatal lethality and disrupt mitochondrial pathways