PSMF1 variants cause a phenotypic spectrum from early-onset Parkinson’s disease to perinatal lethality and disrupt mitochondrial pathways

Dissecting biopathways unveiled by Mendelian gene discovery has provided critical insights into the pathogenesis of Parkinson’s disease (PD) and neurodegeneration, hence catalyzing the identification of potential biomarkers and therapeutic targets. Here, we identify PSMF1 as a new gene implicated in PD and human neurodegeneration. We found that biallelic PSMF1 missense and loss-of-function variants cosegregate with phenotypes from early-onset PD and parkinsonism to perinatal lethal neurodegeneration across 15 unrelated pedigrees with 22 affected subjects, showing clear-cut 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 in patient-derived fibroblasts. Additionally, we develop models of psmf1 knockdown Drosophila 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 that mitochondrial dysfunction contributes to neuronal loss.