Alterations in the neuromuscular junction (NMJ) have recently been reported in motor neuron diseases such as Spinal muscular atrophy (SMA);however, little is known about the pathways that regulate synaptic activity and development in motor neurons. Although transcriptional mechanisms have been shown to regulate critical steps in the development of the nervous system, recent studies have highlighted the importance of the ubiquitin proteasome system (UPS) in the development and maintenance of synaptic connections. By regulating ubiquitin signaling pathways, such as kinase activation and the trafficking and abundance of cellular proteins, the UPS can control developmental transition points during the maturation of the nervous system. However, it is not known how the cell regulates available ubiquitin pools required for these processes. Given the distance that separates the motor neuron cell body and endplate, specialized mechanisms must ensure the stable expression of ubiquitin necessary for axon path finding, synaptic targeting and motor endplate maturation. Our studies now demonstrate that the proteasomal deubiquitinating enzyme Usp14 is required for the postnatal development of the motor neuron endplate. Homozygous axJ mice, which are deficient for Usp14, display a resting tremor, hind limb rigidity, reduced muscle mass and die by 8 weeks of age. These mice do not have ubiquitinated protein aggregates or accelerated neuronal cell death, but instead show ubiquitin loss that correlates with impaired motor endplate maturation during the first two weeks of postnatal development. Restoration of ubiquitin levels in the axJ mice increases body mass and motor function and prevents postnatal lethality, indicating that ubiquitin loss can be a major contributor to neuromuscular disease. Our recent studies also demonstrate ubiquitin loss in a mouse model of SMA, which displays impaired NMJ maturation and function similar to the axJ mice, validating the importance of identifying the developmental pathways regulated by ubiquitin. Our working hypothesis is that Usp14 functions to maintain ubiquitin levels required for the development and activity of mammalian synapses.
The first aim of this proposal will determine the contribution of ubiquitin loss in the axJ mice to the development and activity of the NMJ. In the second aim, we will investigate a newly proposed catalytic-independent function of Usp14 on the proteasome and determine if it is required for development and synaptic transmission at the NMJ.
The third aim i s designed to determine the role of motor neurons and motor endplates in the disease process in the axJ mice.
The final aim will examine the ubiquitin-dependent pathways that control synaptic maturation and function of the NMJ. This proposal will use a combination of genetics and biochemistry to investigate the essential enzymatic functions of Usp14 on the proteasome and determine how changes in the activity of Usp14 alter signaling pathways required for synaptic development and function.
The ubiquitin proteasome system functions to control cellular pathways by regulating protein levels within cells. Since alterations in protein turnover are believed to be central to several chronic neurological diseases, the identification and analysis of components of the ubiquitin proteasome system will provide new insights into the mechanisms of neurological disease and identify potential targets for therapeutic intervention.
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