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.
Systemic and conditional loss of the parkinsonian pyramidal syndrome‐associated protein FBXO7 (PARK15) in mice triggers motor impairment. At the neuronal level, the E3 ligase FBXO7‐SCF associates with proteasomes and regulates their assembly.
FBXO7‐SCF binds to and ubiquitinates the proteasomal subunit PSMA2.
FBXO7 affects the assembly state and activity of the proteasome in the cells including neurons.
Systemic deletion of FBXO7 leads to premature death and motor disabilities.
Deletion of FBXO7 from forebrain and dopaminergic neurons triggers early‐ and late‐onset motor impairment, respectively.
The EMBO Journal (2016) 35: 2008–2025
- Received November 30, 2015.
- Revision received June 13, 2016.
- Accepted July 7, 2016.
- © 2016 The Authors