Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from parkinsonism to perinatal lethality

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 PSMF1 as a gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 18 pedigrees with 25 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/hPI31, 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 may affect proteasomal abundance and assembly, and are associated with alterations of mitochondrial membrane potential, respiration, dynamics and mitophagy in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PI31 loss of function exhibit age-dependent motor impairment, as well as brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice. Collectively, our findings unequivocally link defective PSMF1/hPI31 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as pathogenic contributors.

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Journal
Nature Communications
Published
2026-04-15
DOI
https://doi.org/10.1038/s41467-026-71351-w
Primary Topic
Ubiquitin and proteasome pathways
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article
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article

Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from parkinsonism to perinatal lethality

Simon A. Lowe, Raja Sekhar Nirujogi, Karen Stals, Michael Zech et al.
Nature Communications
Ubiquitin and proteasome pathways
article

Variants in the proteasome regulator PSMF1 cause a phenotypic spectrum from parkinsonism to perinatal lethality

Simon A. Lowe, Raja Sekhar Nirujogi, Karen Stals, Michael Zech, Francesco Cavallieri, Tobias B. Haack, Simone Baiardi, Annarita Scardamaglia, Güneş Kızıltan, Marlène Cassar, Tova Hershkovitz, Marina Svetel, Piero Parchi, Thomas Zöggeler, Stéphanie Efthymiou, Paweł Lis, Başar Bılgıç, Junko Shimazu, Noemí Esteras, Barbara Vona, Matthew Jaconelli, Huma Arshad Cheema, Clarissa Rocca, Thomas Courtin, Anjum Saeed, Ulrich A. Schatz, Guido J. Breedveld, Christelle Tesson, Karin Weiss, Nina Barišić, Vincenzo Bonifati, Linda Sofan, Andrey Y. Abramov, Edoardo Monfrini, Mariasavina Severino, Benjamin O’Callaghan, Jose Angel Obeso, Rebecca Buchert, Robert Steinfeld, Cornelis Blauwendraat, Suzanne Lesage, Sze-Shing Fan, J. H. Hardy, Aida M. Bertoli‐Avella, James E.C. Jepson, Hermann Steller, Christine Fauth, Henry Houlden, Guillaume Cogan, Reza Maroofian, Shahryar Alavi, Marina Volin, Vanessa Pitz, Bülent Elibol, Hülya Tireli, Francesca Magrinelli, Plamena R. Angelova, Chloé Pinon, Ainara Salazar‐Villacorta, K P Bhatia, Sonia Gandhi, Mario Santangelo, Bassem A. Hassan, Muhammad Nadeem Anjum, H. Hanaǧasi, Earny Wei-Sen Ng, Tuğçe Gül-Demirkale, Bedia Samanci, Dario R. Alessi, Gül Yalçin-çakmakli, A Nazlı Başak, B H Y Chung, Issam Azmi Alkhawaja, Alexis Brice, Vinod Varghese, Martin Man-Chun Chui, Anna Ka-Yee Kwong, Michele Tinazzi, Tipu Sultan, PSMF1 Study Group, Monica M. Kurtis, Javeria Raza Alvi, Gülbün A. Yüksel, Peter Bauer, Mary B. Makarious, Sana Iftikhar, Jose A. Rodriguez, Angela Mammana, Alessio Di Fonzo, Tawfiq Froukh, David Murphy, Hadeel Abdollah E. Alrukban
article en

Abstract

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 PSMF1 as a gene implicated in parkinsonism and childhood neurodegeneration. We find that biallelic PSMF1 missense and loss-of-function variants co-segregate with phenotypes from early-onset PD to perinatal lethality with neurological manifestations across 18 pedigrees with 25 affected subjects, showing clear genotype-phenotype correlation. PSMF1 encodes the proteasome regulator PSMF1/hPI31, 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 may affect proteasomal abundance and assembly, and are associated with alterations of mitochondrial membrane potential, respiration, dynamics and mitophagy in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PI31 loss of function exhibit age-dependent motor impairment, as well as brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice. Collectively, our findings unequivocally link defective PSMF1/hPI31 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as pathogenic contributors.

Nature Communications
Universidad San Pablo CEU (ES), University of Verona (IT), Universidad Complutense de Madrid (ES), Centre National de la Recherche Scientifique (FR), National Institutes of Health (US), Riyadh Armed Forces Hospital (SA), Royal Veterinary College (GB), Koç University (TR), University Hospital Centre Zagreb (HR), University of Lahore (PK), Innsbruck Medical University (AT), Philadelphia University (JO), Inserm (FR), Queen Mary University of London (GB), Technion – Israel Institute of Technology (IL), University of Dundee (GB), Chinese University of Hong Kong (HK), Royal Devon & Exeter NHS Foundation Trust (GB), Western Galilee Hospital (IL), Jordan Hospital (JO), The Francis Crick Institute (GB), Rambam Health Care Campus (IL), Istituto Giannina Gaslini (IT), Erasmus MC (NL), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico (IT), University of Health Sciences Lahore (PK), İstanbul Nişantaşı Üniversitesi (TR), Helmholtz Zentrum München (DE), Epilepsy Research UK (GB), Sorbonne Université (FR), Biomedical Research Networking Center on Neurodegenerative Diseases (ES), Azienda Sanitaria Unità Locale di Reggio Emilia (IT), Assistance Publique – Hôpitaux de Paris (FR), MRC Protein Phosphorylation and Ubiquitylation Unit (GB), National Institute of Neurological Disorders and Stroke (US), Istanbul University-Cerrahpaşa (TR), Universitätsmedizin Göttingen (DE), Pitié-Salpêtrière Hospital (FR), HM Hospitales (ES), University Hospital HM Puerta del Sur (ES), Istituto delle Scienze Neurologiche di Bologna (IT), Haydarpaşa Numune Eğitim ve Araştırma Hastanesi (TR), Sağlık Bilimleri Üniversitesi (TR), National Institute on Aging (US), Institute for Advanced Study (DE), Centogene (Germany) (DE), California Adaptive Rowing Program (US), Hospital Ruber Internacional (ES), Center for Genomic Science (IT), National Hospital for Neurology and Neurosurgery (GB), Genomics (United Kingdom) (GB), Institut du Cerveau (FR), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University College London (GB), Technical University of Munich (DE), Hacettepe University (TR), Istanbul University (TR), University of Göttingen (DE), Charité - Universitätsmedizin Berlin (DE), University of Tübingen (DE), Rockefeller University (US), University of Hong Kong (HK), Medical Research Council (GB), University of Bologna (IT)
Michael J. Fox Foundation for Parkinson's Research, American Parkinson Disease Association, National Institute for Health and Care Research, Parkinson's UK
Good health and well-being
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Ubiquitin and proteasome pathways
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