Session Information
Date: Monday, June 20, 2016
Session Title: Parkinsonism, MSA, PSP (secondary and parkinsonism-plus)
Session Time: 12:30pm-2:00pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: To model Parkinsonian-pyramidal syndrome (PARK15) in mice and investigate the impact of loss of F-box only protein 7 (FBXO7) in neurons on proteasomal activity.
Background: Mutations in FBXO7 has been shown to cause Parkinsonian-pyramidal syndrome (PARK15) in several families. FBXO7 is an E3 ubiquitin ligase, but little is known about its function in neurons and the mechanism by which its dysfunction causes Parkinsonian-pyramidal syndrome.
Methods: We generated conventional and conditional FBXO7 knockout mice and evaluated their motor phenotype with behavioral tests. We then used immunohistochemistry and HPLC analyses to assess the integrity of the dopaminergic system in these mice. In addition we used proteasomal activity assays to investigate the role of FBXO7 in proteasomal function.
Results: Conventional FBXO7 knockout mice show early-onset weakness and premature death. The catecholaminergic FBXO7 knockout mouse model, TH-Cre FBXO7 fl/fl, shows progressive loss of motor function and reduced levels of dopamine in the striatum without cell-body loss. The forebrain-specific FBXO7 knockout mouse model, NEX-Cre FBXO7 fl/fl, presents with spasticity, hyper-reflexia and severe motor dysfunction. Loss of FBXO7 in immortalized cell-lines results in reduced proteasomal activity. This finding is replicated in brain-tissue of FBXO7 knockout mice.
Conclusions: We have shown that loss of FBXO7 leads to reduced proteasomal activity, suggesting a role for FBXO7 in proteasomal regulation. We also provide behavioral characterization of three novel FBXO7 knockout mouse lines showing deficits that can be translated into parkinsonism and pyramidal signs and symptoms. Further investigation of these models might provide insight into mechanisms underlying Parkinsonian-pyramidal syndrome. In addition, the striking motor phenotype of these animals might present a useful model for test of therapeutic agents.
To cite this abstract in AMA style:
S. Vingill, D. Brockelt, N. Schwedhelm-Domeyer, L. Tatenhorst, S. Goebbels, P. Lingor, K.A. Nave, J. Stegmueller. Loss of FBXO7 (PARK15) leads to disturbances in proteasomal function and models parkinsonism-like and pyramidal symptoms in mice [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/loss-of-fbxo7-park15-leads-to-disturbances-in-proteasomal-function-and-models-parkinsonism-like-and-pyramidal-symptoms-in-mice/. Accessed May 18, 2025.« Back to 2016 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/loss-of-fbxo7-park15-leads-to-disturbances-in-proteasomal-function-and-models-parkinsonism-like-and-pyramidal-symptoms-in-mice/