PSMF1variants cause a phenotypic spectrum from early-onset Parkinson’s disease to perinatal lethality by disrupting mitochondrial pathways
Author:
Magrinelli FrancescaORCID, Tesson ChristelleORCID, Angelova Plamena R.ORCID, Salazar-Villacorta AinaraORCID, Rodriguez Jose A.ORCID, Scardamaglia AnnaritaORCID, Chung Brian Hon-YinORCID, Jaconelli MatthewORCID, Vona BarbaraORCID, Esteras NoemiORCID, Kwong Anna Ka-YeeORCID, Courtin ThomasORCID, Maroofian RezaORCID, Alavi ShahryarORCID, Nirujogi RajaORCID, Severino MariasavinaORCID, Lewis Patrick A.ORCID, Efthymiou StephanieORCID, O’Callaghan BenjaminORCID, Buchert RebeccaORCID, Sofan LindaORCID, Lis PawelORCID, Pinon ChloéORCID, Breedveld Guido J.ORCID, Chui Martin Man-ChunORCID, Murphy DavidORCID, Pitz VanessaORCID, Makarious Mary B.ORCID, Cassar MarleneORCID, Hassan Bassem A.ORCID, Iftikhar SanaORCID, Rocca ClarissaORCID, Bauer PeterORCID, Tinazzi MicheleORCID, Svetel MarinaORCID, Samanci BediaORCID, Hanağası Haşmet A.ORCID, Bilgiç BasarORCID, Obeso José A.ORCID, Kurtis Monica M.ORCID, Cogan GuillaumeORCID, Başak Ayşe NazlıORCID, Kiziltan GüneşORCID, Gül TuğçeORCID, Yalçın GülORCID, Elibol BülentORCID, Barišić NinaORCID, Ng Earny Wei-SenORCID, Fan Sze-ShingORCID, Hershkovitz TovaORCID, Weiss KarinORCID, Raza Alvi JaveriaORCID, Sultan TipuORCID, Azmi Alkhawaja IssamORCID, Froukh TawfiqORCID, E Alrukban Hadeel AbdollahORCID, Fauth ChristineORCID, Schatz Ulrich A.ORCID, Zöggeler ThomasORCID, Zech MichaelORCID, Stals KarenORCID, Varghese VinodORCID, Gandhi SoniaORCID, Blauwendraat CornelisORCID, Hardy John A.ORCID, Lesage SuzanneORCID, Bonifati VincenzoORCID, Haack Tobias B.ORCID, Bertoli-Avella Aida M.ORCID, Steinfeld RobertORCID, Alessi Dario R.ORCID, Steller HermannORCID, Brice AlexisORCID, Abramov Andrey Y.ORCID, Bhatia Kailash P.ORCID, Houlden HenryORCID
Abstract
AbstractDissecting 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 identifyPSMF1as a new gene implicated in PD and childhood neurodegeneration. We find that biallelicPSMF1missense 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.PSMF1encodes 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 thatPSMF1variants impair mitochondrial membrane potential, dynamics and mitophagy in patient-derived fibroblasts. Additionally, we develop models ofpsmf1knockdownDrosophilaandPsmf1conditional 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.
Publisher
Cold Spring Harbor Laboratory
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