Elucidating the functions of the E3 ubiquitin ligase FBXO7 - with a particular focus on myelinating cells

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Myelinating glial cells provide the means for the rapid propagation of action potentials in neurons. The integrity of these cells and thus the maintenance of the axon-glial interaction is critically dependent on the their protein homeostasis ensured by the ubiquitin proteasome system (UPS). The E3 ubiquitin ligase FBXO7 has been associated with juvenile parkinsonism and the parkinsonism-related white matter disorder multiple system atrophy (MSA). While we my lab has established that FBXO7 is critically important in neurons, the role of FBXO7 in myelinating cells remains to be characterized. We will address the following question in aim 1: How does the loss of FBXO7 affect the integrity of myelinating cells of the CNS and PNS? In aim 2 and 3, we will investigate the role of FBXO7 in proteasome and mitochondrial function, respectively, as our preliminary results point towards regulatory functions of FBXO7 in both systems. Hence, aim 2 is as follows: What are the molecular underpinnings of the biochemical relationship between FBXO7 and the proteasomal subunit PSMA2 in proteasome regulation? Is this true for myelination cells? Aim 3 expands the understanding of FBXO7 functions and addresses the following question: Does the FBXO7/MAP1B interaction affect microtubule dynamics and/or mitochondrial integrity in myelinating cells?