PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality by disrupting mitochondrial pathways

• Published in: medRxiv : the preprint server for health sciences
• Main Authors: Magrinelli, Francesca, Tesson, Christelle, Angelova, Plamena R, Salazar-Villacorta, Ainara, Rodriguez, Jose A, Scardamaglia, Annarita, Chung, Brian Hon-Yin, Jaconelli, Matthew, Vona, Barbara, Esteras, Noemi, Kwong, Anna Ka-Yee, Courtin, Thomas, Maroofian, Reza, Alavi, Shahryar, Nirujogi, Raja, Severino, Mariasavina, Lewis, Patrick A, Efthymiou, Stephanie, O'Callaghan, Benjamin, Buchert, Rebecca, Sofan, Linda, Lis, Pawel, Pinon, Chloé, Breedveld, Guido J, Chui, Martin Man-Chun, Murphy, David, Pitz, Vanessa, Makarious, Mary B, Cassar, Marlene, Hassan, Bassem A, Iftikhar, Sana, Rocca, Clarissa, Bauer, Peter, Tinazzi, Michele, Svetel, Marina, Samanci, Bedia, Hanağası, Haşmet A, Bilgiç, Basar, Obeso, José A, Kurtis, Monica M, Cogan, Guillaume, Başak, Ayşe Nazlı, Kiziltan, Güneş, Gül, Tuğçe, Yalçın, Gül, Elibol, Bülent, Barišić, Nina, Ng, Earny Wei-Sen, Fan, Sze-Shing, Hershkovitz, Tova, Weiss, Karin, Raza Alvi, Javeria, Sultan, Tipu, Azmi Alkhawaja, Issam, Froukh, Tawfiq, E Alrukban, Hadeel Abdollah, Fauth, Christine, Schatz, Ulrich A, Zöggeler, Thomas, Zech, Michael, Stals, Karen, Varghese, Vinod, Gandhi, Sonia, Blauwendraat, Cornelis, Hardy, John A, Lesage, Suzanne, Bonifati, Vincenzo, Haack, Tobias B, Bertoli-Avella, Aida M, Steinfeld, Robert, Alessi, Dario R, Steller, Hermann, Brice, Alexis, Abramov, Andrey Y, Bhatia, Kailash P, Houlden, Henry
• Format: Journal Article
• Language: English
• Published: United States 20.06.2024

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 as a new gene implicated in PD and childhood neurodegeneration. We find that biallelic missense and loss-of-function variants co-segregate with phenotypes from early-onset PD and parkinsonism to perinatal lethality with neurological manifestations across 15 unrelated pedigrees with 22 affected subjects, showing clear genotype-phenotype correlation. 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 variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models of knockdown 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 mitochondrial dysfunction as a mechanistic contributor.