Function of the oxidoreductase PYROXD1 in axon regeneration

项目总结/文摘

Project Summary/Abstract Through axon regeneration, neurons restore function after injury. This conserved, complex process requires numerous cellular pathways including support of mitochondrial function and RNA processing. Mitochondria function is implicated in numerous neurological disorders, and dysfunction of mitochondria contributes to oxidative stress, a hallmark of aging. However, the role of the oxidative environment in axon regeneration has not been well characterized. Oxidoreductases are a diverse class of enzymes that regulate the oxidative environment of neurons. The oxidoreductase PYROXD1 is important for human health, and loss of PYROXD1 disrupts mitochondrial function and RNA-ligation by RtcB during the unfolded protein response. We found that PYROXD1 is necessary for axon regeneration; however, the mechanism by which PYROXD1 promotes regeneration is unknown. This proposal will elucidate the mechanism of PYROXD1 in axon regeneration in two independent aims. In Aim 1, the role of PYROXD1 in mitochondria function and localization in axons during injury will be determined. Mitochondria are critical for axon regeneration, and PYROXD1 is required for normal mitochondria function. Aim 1 will establish the relationship between PYROXD1 and mitochondria during axon regeneration, and will examine a suite of clinically-significant PYROXD1 mutations in this process. In Aim 2, the role of PYROXD1-protection of the RNA-ligase RtcB will be clarified. RtcB inhibits axon regeneration via a novel mechanism of non-canonical cytoplasmic splicing during the unfolded protein response. RtcB is dependent on copper, and this dependence makes it sensitive to inactivation in oxidative environments. Aim 2 will determine the sensitivity of RtcB to redox environment in vivo and define the relationship among PYROXD1, RtcB, and the unfolded protein response gene xbp-1 in regeneration. Upon completion of this fellowship, the trainee will have received extensive training in a supportive and collaborate environment. The project will further the trainee’s technical skills, critical thinking abilities, and independence in preparation for an academic career in molecular neuroscience. The results of this project will shed light on the importance of oxidative environment, mitochondria function, and RNA processing for successful axon regeneration.