Neurotrophins play a critical role in supporting neuronal viability throughout life. This role requires that neurotrophins promote the health of cel bodies and also the health of extensive dendrites and axons characteristic of mature neurons. Recent studies have demonstrated that the mechanisms which promote axonal viability only partially overlap with those that regulate cell body survival. The proposed work focuses on neurotrophin regulation of axonal viability, and the role of the specialized Bcl2 family member Bcl-w in this process. Work from the sponsor's lab has demonstrated that Bcl-w mRNA and protein are expressed at high levels in axons of dorsal root ganglia (DRG) sensory neurons, and that loss of Bcl-w results in selective degeneration of axons in vivo. Furthermore, Bcl-w expression is regulated by neurotrophin stimulation, and in particular, by neurotrophin stimulation of the axons. Together, these data suggest that Bcl-w is a specialized axonal survival factor that mediates the effects of neurotrophins on axonal viability. The two aims presented in this research proposal build on previous studies from the sponsor, and will directly test how neurotrophins regulate Bcl-w mRNA and protein in axons, in order to understand mechanisms for maintaining axonal health.
Aim1 : To test the hypothesis that the 3'UTR is critical for targeting bcl-w mRNA to axons. To do this, the bcl-w 3'UTR will be tested for its abilty to localize a reporter sequence to axons.
Aim 2 : To test the hypothesis that neurotrophins regulate local translation of bcl-w in axons. To do so, a novel method which provides several advantages over current techniques of studying translation in axons will be used. In preliminary studies I have demonstrated effective use of this method in DRG neurons and compartmented cultures. Local synthesis of Bcl-w in axons may provide a mechanism for mediating the sustained effect of neurotrophins on axonal viability and maintenance. This work will develop our understanding of how neurotrophins promote survival and health of distinct cellular compartments and the mechanisms by which axons are maintained throughout life. Understanding the mechanisms by which neurotrophins regulate axonal viability are essential to understanding mechanisms of axonal degeneration and finding therapeutic targets for disorders of neurodegeneration.
Growth factors, called neurotrophins, are required for the survival and maintenance of neurons throughout an individual's lifetime. The proposed research will develop our understanding for the specific mechanisms by which neurotrophins support health of neurons with long axons, such as peripheral sensory neurons, which carry vital information about the environment. This work will be critical for understanding mechanisms of axonal degeneration and for developing therapeutic treatments for neurodevelopmental and neurodegenerative disorders.
|Cosker, Katharina E; Fenstermacher, Sara J; Pazyra-Murphy, Maria F et al. (2016) The RNA-binding protein SFPQ orchestrates an RNA regulon to promote axon viability. Nat Neurosci 19:690-696|
|Cosker, Katharina E; Pazyra-Murphy, Maria F; Fenstermacher, Sara J et al. (2013) Target-derived neurotrophins coordinate transcription and transport of bclw to prevent axonal degeneration. J Neurosci 33:5195-207|