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