Characterization of FBXO7 (PARK15) knockout mice modeling Parkinsonian-Pyramidal Syndrome
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EnglishThe second most common neurodegenerative disease, Parkinson’s disease (PD), is caused by loss of dopaminergic neurons in the substantia nigra leading to impaired motor control. Genetic analyses have revealed recessively and dominantly inherited mutations in the so-called PARK genes that cause symptoms reminiscent of those of PD. Mutations in the FBXO7 gene (PARK15) have been linked to several families presenting with Parkinsonian-Pyramidal Syndrome, but its precise role in neurons remains unknown. Proteasomal dysfunction has previously been linked to PD. Owing to the previously published finding that FBXO7 interacts with the proteasomal modulator PI31, I investigated the role of FBXO7 in proteasomal regulation and found in loss-of-function experiments that FBXO7 promotes proteasome activity. To model the PARK15 syndrome in mice, we generated a conventional FBXO7 knockout mouse line. With behavioral experiments, I showed that these mice present early onset motor defects and premature death. As FBXO7 is ubiquitously expressed in the brain, we dissected the pyramidal and Parkinsonian phenotype using a conditional knockout strategy. I found that loss of FBXO7 in pyramidal forebrain neurons caused severe motor deficits reminiscent of the pyramidal symptoms seen in PARK15 patients, in addition to stereotypic behavior. I could show that the glutamatergic transporter level was downregulated in the striatum of these mice, along with an increase in dopamine. On the other hand, loss of FBXO7 in murine catecholaminergic neurons lead to a progressive loss of fine motor control with reduced ambulation in the end stage, which can be interpreted as a Parkinsonian phenotype. This was accompanied by a significant decrease of striatal dopamine, without neuronal loss. Taken together, this study shows FBXO7 as a regulator of the 26S proteasome and characterizes novel mouse models for investigation of Parkinsonian-Pyramidal Syndrome.
Parts of this work was published after the thesis defense in EMBO Journal as "Loss of FBXO7 (PARK15) results in reduced proteasome activity and models a parkinsonism-like phenotype in mice." Copyright © 2016 by John Wiley Sons, Inc. Reprinted by permission of John Wiley & Sons, Inc.