medRxiv : the preprint server for health sciences · 2025

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

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

Аннотация

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 novel 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 17 pedigrees with 24 affected subjects, showing clear 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, and may affect proteasomal abundance and assembly in patient-derived fibroblasts. Furthermore, Drosophila and mouse models of PSMF1 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 to early-onset parkinsonism and neurodegeneration, and suggest proteasomal and mitochondrial dysfunction as mechanistic contributors.

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

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Аннотация