Dataset Information

PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson’s disease to perinatal lethality and disrupt mitochondrial pathways

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skin, Fibroblast

DISEASE(S): Parkinson's Disease

SUBMITTER: Matthew Jaconelli

LAB HEAD: Prof. Dario

PROVIDER: PXD053147 | Pride | 2026-03-03

REPOSITORIES: Pride

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			Action	DRS
	FL_20240226_MJ_PSFM1_1300_A.raw	Raw
	FL_20240226_MJ_PSFM1_1300_B.raw	Raw
	FL_20240226_MJ_PSFM1_1300_C.raw	Raw
	FL_20240226_MJ_PSFM1_1300_D.raw	Raw
	FL_20240226_MJ_PSFM1_1301_A.raw	Raw

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Publications

Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality and disrupt mitochondrial function.

Magrinelli Francesca F Tesson Christelle C Angelova Plamena R PR Rodriguez Jose A JA Scardamaglia Annarita A O'Callaghan Benjamin B Lowe Simon A SA Salazar-Villacorta Ainara A Chung Brian Hon-Yin BH Jaconelli Matthew M Vona Barbara B Esteras Noemi N Mammana Angela A Shimazu Junko J Kwong Anna Ka-Yee AK Courtin Thomas T Alavi Shahryar S Maroofian Reza R Nirujogi Raja R Severino Mariasavina M Monfrini Edoardo E Rocca Clarissa C Lewis Patrick A PA Efthymiou Stephanie S Buchert Rebecca R Sofan Linda L Lis Pawel P Pinon Chloé C Breedveld Guido J GJ Chui Martin Man-Chun MM Murphy David D Pitz Vanessa V Makarious Mary B MB Baiardi Simone S Volin Marina M Cassar Marlene M Hassan Bassem A BA Iftikhar Sana S Bauer Peter P Tinazzi Michele M Svetel Marina M Samanci Bedia B Hanağası Haşmet A HA Bilgiç Basar B Cavallieri Francesco F Santangelo Mario M Obeso José A JA Kurtis Monica M MM Cogan Guillaume G Kiziltan Güneş G Gül-Demirkale Tuğçe T Tireli Hülya H Yüksel Gülbün A GA Yalçın-Cakmakli Gül G Elibol Bülent B Barišić Nina N Ng Earny Wei-Sen EW Fan Sze-Shing SS Hershkovitz Tova T Weiss Karin K Alvi Javeria Raza JR Sultan Tipu T Alkhawaja Issam Azmi IA Froukh Tawfiq T Alrukban Hadeel Abdollah E HAE Fauth Christine C Schatz Ulrich A UA Zöggeler Thomas T Zech Michael M Stals Karen K Varghese Vinod V Gandhi Sonia S Blauwendraat Cornelis C Hardy John A JA Di Fonzo Alessio A Bonifati Vincenzo V Haack Tobias B TB Bertoli-Avella Aida M AM Lesage Suzanne S Başak Ayşe Nazlı AN Steinfeld Robert R Parchi Piero P Jepson James E C JEC Alessi Dario R DR Brice Alexis A Steller Hermann H Abramov Andrey Y AY Bhatia Kailash P KP Houlden Henry H

medRxiv : the preprint server for health sciences 20250721

Dissecting biological pathways highlighted by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson's disease (PD) and neurodegeneration. This approach ultimately catalyzes the identification of potential biomarkers and therapeutic targets. Here, we identify <i>PSMF1</i> as a novel gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic <i>PSMF1</i> missense and loss-of-function variants co-segregate with phenotypes from early- ...[more]

PMID: 39148840

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