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 helixloop-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.
Brain-derived neurotrophic factor (BDNF) is widely reported to enhance synaptic vesicle (SV) exocytosis and neurotransmitter release. But it is still unclear whether BDNF enhances SV recycling at excitatory terminals only, or at both excitatory and inhibitory terminals. In the present study, in a direct comparison using cultured rat hippocampal neurons, we demonstrate that BDNF enhances both spontaneous and activity-dependent neurotransmitter release from excitatory terminals, but not from inhibitory terminals. BDNF treatment for 5 min or 48 h increased both spontaneous and activity-induced anti-synaptotagmin1 (SYT1) antibody uptake at excitatory terminals marked with vGluT1. Conversely, BDNF treatment did not enhance spontaneous or activity-induced uptake of anti-SYT1 antibodies in inhibitory terminals marked with vGAT. Time-lapse imaging of FM1-43 dye destaining in excitatory and inhibitory terminals visualized by post-hoc immunostaining of vGluT1 and vGAT also showed the same result: The rate of spontaneous and activity-induced destaining was increased by BDNF at excitatory synapses, but not at inhibitory synapses. These data demonstrate that BDNF enhances SV exocytosis in excitatory but not inhibitory terminals. Moreover, BDNF enhanced evoked SV exocytosis, even if vesicles were loaded under spontaneous vesicle recycling conditions. Thus, BDNF enhances both spontaneous and activity-dependent neurotransmitter release on both short and long time-scales, by the same mechanism.
Parkinson's disease (PD) is a debilitating movement disorder. Growing evidence associates genes with familial forms of the disease. Recently, gene mutations in the FBXO7 (PARK15) gene have been identified in patients with early-onset parkinsonism symptoms and pyramidal tract signs. PARK15 encodes for the E3 ubiquitin ligase FBXO7, whose function in the brain remains to be elucidated. In this study, I report that systemic loss of FBXO7 in mice results in an early-onset motor phenotype and premature death, reminiscent of the PARK15 patients. In neuropatholgical analyses, I find a regional increase in cell death and widespread astrogliosis. At the molecular level, I demonstrate the binding of FBXO7 to the proteasomal core subunit PSMA2 and identify PSMA as non-proteolytic ubiquitination substrate.Interestingly, I show that loss of FBXO7 in the brain leads to reduced proteasome activity as a consequence of defective proteasome integrity. Taken together, I established an FBXO7dependent mechanism of proteasome regulation in neurons, which provides novel insight into the role of the UPS in PD. PARK7 DJ1 1p36.23 recessive early onset 1.1.3 Mutations on FBXO7 (PARK15) Autosomal-recessive mutations of FBXO7 (F-box protein 7; PARK15) were first reported in 2008 (Shojaee et al., 2008) and subsequently associated with hereditary parkinsonism in 2009 (Di Fonzo et al., 2009). Since then, mutations in the gene have been identified in several families (Table 1.2). PARK15 patients display a juvenile onset of the disease with a broad spectrum of symptoms. While most of the so far reported cases show a parkinsonian-pyramidal syndrome (PPS), the phenotypes range from only pyramidal involvement (Shojaee et al., 2008) over a mixed contribution as parkinsonian-pyramidal syndrome (PPS) (Di Fonzo et al., 2009) to only parkinsonism (which also includes also a broad spectrum of disorders) (Lohmann et al., 2015). All patients treated with the amino acid behavioral disturbances dyskinesia, behavioral disturbances B, bradykinesia; R, rigidity; RT, resting tremor; PI, postural instabilityThe ubiquitin proteasome system (UPS). The E1 enzyme activates ubiquitin (Ub) in an ATP dependent manner and facilitates the transfer to the E2 enzyme. Subsequently, the E3 enzyme binds both, Ub conjugate as well as the substrate protein to facilitate ubiquitin attachment on the substrate. Ubiquitinated proteins are then either destined for proteasomal degradation or altered in their protei The E1 enzyme activates ubiquitin (Ub) in an ATPenzyme. Subsequently, the E3 enzyme binds both, Ub conjugate as well as the substrate protein to facilitate ubiquitin attachment on the substrate. Ubiquitinated proteins are then either destined for proteasomal degradation or altered in their protein function.Different assembly forms of the proteasome. The 20S core particle consists of four heptameric rings of α and β subunits. One or two 19S regulatory particles, together with the 20S core particle compose competent 26S or 30S proteasome holoenzyme.-linked polyubiquitination, ...
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