The long-term goal of this project is to determine mechanisms by which synaptic transmission is regulated by cellular stress pathways. The motivation of this project is twofold. First, stress plays a critical role in cognitive dysfunction and neurodegeneration associated with neurodegenerative diseases. Second, although much has been learned about how cellular responses to stress can promote neuronal survival, far less is known about how these responses can regulate neuronal function. We propose to characterize the role of a stress response pathway that mediates cellular responses to oxidative stress in regulating synaptic function using C. elegans as a model system. We previously identified a new protein that is conserved in vertebrates, WDR-23, in a functional genomic screen for genes required for synaptic transmission at the neuromuscular junction. We found that WDR-23 promotes the secretion of neurotransmitter from presynaptic terminals by antagonizing the activity of the transcription factor SKN-1. SKN-1 is the ortholog of the mammalian NF-E2 related factor (Nrf) family of transcription factors, which are critical for protecting neurons form the neurodegenerative effects of oxidative stress. We found that skn-1 activity is required for proper neurotransmission and for expression of a neuron-specific gene, acr-2, which encodes an acetylcholine receptor subunit of unknown function. Here we propose to test the hypothesis that SKN-1 regulates synaptic transmission in response to stress. First, we will determine how SKN-1 activity is negatively regulated by WDR-23 and by stress pathways in neurons. Second, we will identify the environmental and cellular stress pathways that activate SKN-1 in neurons. Third, we will determine how SKN-1-activated transcriptional programs generate changes in neurotransmitter secretion and synaptic function. These experiments will provide insights into the molecular mechanisms by which the SKN-1/Nrf stress response pathway regulates synaptic function. In summary, this work will establish a novel role for SKN-1/Nrf-mediated transcriptional programs in regulating synaptic transmission, and should provide insights into how stress impacts synaptic dysfunction associated with neurodegenerative diseases.

Public Health Relevance

Many neurodegenerative disorders, such as Alzheimer's and Parkinson's disease are thought to be caused by toxins that accumulate in brain cells as the result of normal ageing. Here we propose to study how a natural system that the body uses to remove these toxins can impact normal brain cell function, and how it can be used to delay or prevent the onset of these diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Talley, Edmund M
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University of Southern California
Anatomy/Cell Biology
Schools of Medicine
Los Angeles
United States
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Kim, Sungjin; Sieburth, Derek (2018) Sphingosine Kinase Activates the Mitochondrial Unfolded Protein Response and Is Targeted to Mitochondria by Stress. Cell Rep 24:2932-2945.e4
Kim, Sungjin; Sieburth, Derek (2018) Sphingosine Kinase Regulates Neuropeptide Secretion During the Oxidative Stress-Response Through Intertissue Signaling. J Neurosci 38:8160-8176
Shen, Hongying; Giordano, Francesca; Wu, Yumei et al. (2014) Coupling between endocytosis and sphingosine kinase 1 recruitment. Nat Cell Biol 16:652-62
Staab, Trisha A; Evgrafov, Oleg; Egrafov, Oleg et al. (2014) Regulation of synaptic nlg-1/neuroligin abundance by the skn-1/Nrf stress response pathway protects against oxidative stress. PLoS Genet 10:e1004100
Wang, Han; Girskis, Kelly; Janssen, Tom et al. (2013) Neuropeptide secreted from a pacemaker activates neurons to control a rhythmic behavior. Curr Biol 23:746-54
Pickering, Andrew M; Staab, Trisha A; Tower, John et al. (2013) A conserved role for the 20S proteasome and Nrf2 transcription factor in oxidative stress adaptation in mammals, Caenorhabditis elegans and Drosophila melanogaster. J Exp Biol 216:543-53
Chan, Jason P; Staab, Trisha A; Wang, Han et al. (2013) Extrasynaptic muscarinic acetylcholine receptors on neuronal cell bodies regulate presynaptic function in Caenorhabditis elegans. J Neurosci 33:14146-59
Wang, Han; Sieburth, Derek (2013) PKA controls calcium influx into motor neurons during a rhythmic behavior. PLoS Genet 9:e1003831
Staab, Trisha A; Griffen, Trevor C; Corcoran, Connor et al. (2013) The conserved SKN-1/Nrf2 stress response pathway regulates synaptic function in Caenorhabditis elegans. PLoS Genet 9:e1003354
Chan, Jason P; Sieburth, Derek (2012) Localized sphingolipid signaling at presynaptic terminals is regulated by calcium influx and promotes recruitment of priming factors. J Neurosci 32:17909-20

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