title: Loss of FBXO7 (PARK15) results in reduced proteasome activity and models a parkinsonism-like phenotype in mice.
abstract: Mutations in the FBXO7 (PARK15) gene have been implicated in a juvenile form of parkinsonism termed parkinsonian pyramidal syndrome (PPS), characterized by Parkinsonian symptoms and pyramidal tract signs. FBXO7 (F-box protein only 7) is a subunit of the SCF (SKP1/cullin-1/F-box protein) E3 ubiquitin ligase complex, but its relevance and function in neurons remain to be elucidated. Here, we report that the E3 ligase FBXO7-SCF binds to and ubiquitinates the proteasomal subunit PSMA2. In addition, we show that FBXO7 is a proteasome-associated protein involved in proteasome assembly. In FBXO7 knockout mice, we find reduced proteasome activity and early-onset motor deficits together with premature death. In addition, we demonstrate that NEX (neuronal helix-loop-helix protein-1)-Cre-induced deletion of the FBXO7 gene in forebrain neurons or the loss of FBXO7 in tyrosine hydroxylase (TH)-positive neurons results in motor defects, reminiscent of the phenotype in PARK15 patients. Taken together, our study establishes a vital role for FBXO7 in neurons, which is required for proper motor control and accentuates the importance of FBXO7 in proteasome function.
authors: Cellular and Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany Neuroscience, International Max Planck Research School, Göttingen, Germany.
authors: Siv
authors: S
authors: Vingill
authors: Cellular and Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany Neuroscience, International Max Planck Research School, Göttingen, Germany.
authors: David
authors: D
authors: Brockelt
authors: European Neuroscience Institute (ENI), Göttingen, Germany.
authors: Camille
authors: C
authors: Lancelin
authors: Neurology, University Medical Center, Göttingen, Germany Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CMPB), Göttingen, Germany.
authors: Lars
authors: L
authors: Tatenhorst
authors: Cellular and Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany Neuroscience, International Max Planck Research School, Göttingen, Germany Department of Neurology, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Guergana
authors: G
authors: Dontcheva
authors: Proteomics Facility, Interdisciplinary Center for Clinical Research (IZKF) Aachen, Medical Faculty, RWTH Aachen, Aachen, Germany.
authors: Christian
authors: C
authors: Preisinger
authors: Cellular and Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors: Nicola
authors: N
authors: Schwedhelm-Domeyer
authors: Cellular and Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany Neuroscience, International Max Planck Research School, Göttingen, Germany Department of Neurology, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Sabitha
authors: S
authors: Joseph
authors: Light Microscopy Facility, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors: Miso
authors: M
authors: Mitkovski
authors: Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors: Sandra
authors: S
authors: Goebbels
authors: Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CMPB), Göttingen, Germany Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Göttingen, Germany.
authors: Klaus-Armin
authors: KA
authors: Nave
authors: Department of Neurology, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Jörg B
authors: JB
authors: Schulz
authors: European Neuroscience Institute (ENI), Göttingen, Germany Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CMPB), Göttingen, Germany Section Neurobiological Research, Department of Neurology, University Hospital, RWTH Aachen, Aachen, Germany.
authors: Till
authors: T
authors: Marquardt
authors: Neurology, University Medical Center, Göttingen, Germany Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CMPB), Göttingen, Germany.
authors: Paul
authors: P
authors: Lingor
authors: Cellular and Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Göttingen, Germany Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CMPB), Göttingen, Germany Department of Neurology, University Hospital, RWTH Aachen, Aachen, Germany jstegmueller@ukaachen.de.
authors: Judith
authors: 0000-0003-4172-7778
authors: J
authors: Stegmüller
mesh_terms: D000818:Animals; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D055786:Gene Knockout Techniques; D018345:Mice, Knockout; D020734:Parkinsonian Disorders / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C568633:FBXO7 protein, mouse; D046988:Proteasome Endopeptidase Complex
keywords: FBXO7; PARK15; PSMA2; parkinsonism; ubiquitination