Regulation of brain glial cell functions by extracellularly released mitochondrial transcription factor A and microparticles

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The brain contains neurons and non-neuronal cells called glia. It is increasingly evident that glia are critical for maintaining the normal functioning of the brain and spinal cord. Glia actively sample their surrounding environment responding to changes in the functional status of neighbouring cells, and regulate functions of surrounding cells by releasing a range of mediators. Very little is known about the mediators that are used for intercellular signaling between neurons and glia as well as between glial cells themselves under normal physiological conditions. The LONG-TERM OBJECTIVE of my NSERC-funded research program is to address this knowledge gap by characterizing novel intercellular signaling mediators in the brain and studying their physiological roles. With funding from a previous Discovery Grant, I have identified two novel central nervous system (CNS) mediators involved in intercellular signaling: mitochondrial transcription factor A (Tfam), an intracellular protein, which could be released into the extracellular space; and microparticles (MPs), which are small membrane vesicles that are released by CNS cells. Our preliminary data show that both these mediators affect select glial cell functions. The GOAL over the next five years is to examine the molecular mechanisms involved in regulation of glial functions by Tfam and MPs. It is my hypothesis that these two mediators participate in the signaling between different CNS cell types, and are critical for maintaining brain tissue homeostasis.   Specifically, my group will characterize the effects of Tfam and MPs on the two main glial cell types, astrocytes and microglia. We will measure different glial responses such as production of cytokines and reactive oxygen species by using cultured brain-derived glial cells and model cell lines. We will also study glial cell responses to Tfam and MP injections into animal brain. Our preliminary data show that the functional state of glial cells releasing MPs influences their effects on target cells. This may be a novel mechanism of physiological interglial signaling, which will be studied in detail. In addition, we will employ proteomics techniques to compare global changes in the mixture of proteins secreted by glial cells in response to stimulation by Tfam and MPs. The key outcomes include (1) identifying the receptors and intracellular signaling pathways engaged by Tfam and MPs; (2) determining the part of the Tfam molecule responsible for interacting with the cellular receptors; and (3) discovering additional signaling molecules that are released by glia in response to Tfam and MPs. The proposed research program will significantly advance the knowledge about the brain network of intercellular signaling molecules used to maintain CNS homeostasis, which could also lead to practical applications through the identification of molecular targets for altering or improving brain function.