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The Role of the Polarity Protein Par-1/MARK in Regulating Microglia Activation

by
Victoria Lynn DiBona
B.S. Biochemistry, Rutgers University - 2006

Advisor: Huaye Zhang, Ph.D.

Center for Advanced Biotechnology & Medicine (CABM)
Seminar Room 010
Piscataway

Thursday, September 7, 2017
2;00 P.M.


Abstract

The central nervous system (CNS) is composed of diverse cell types. Of these, microglia arise from a unique monocyte lineage. They migrate into the CNS early in development and take on the role of the brainís resident immune cells. Microglia are multi-functioning by responding not only in an immune activated cell capacity, but also as a contributing member in maintaining overall CNS health and function in their ramified state. However, there is a lack of mechanistic understanding of these dual roles of microglia in both the activated and ramified states.

Par1/MARK is a Ser/Thr kinase that regulates polarity establishment in many different cellular contexts. Interestingly, many of the targets of Par1 are proteins important for microtubule and actin dynamics, which are in turn essential for microglia functions such as chemotaxis and phagocytosis. However, whether Par1 plays a role in microglia functions was unknown.

Here we show that primary microglia depleted of Par1 displayed an amoeboid morphology and phagocytized more neuronal particles, both hallmarks of microglia activation. Next, utilizing a Par1b/MARK2 knockout mouse line, we found an increased microglia density in Par1b Heterozygous (Het) (+/-) mice compared to wild-type (WT) (+/+) controls throughout development. In addition, P5 Het (+/-) mice had an altered morphology and increased phagocytosis capacity. Further, adult (WT) (+/+) and (Het) (+/-) mice were subjected to a controlled cortical impact (CCI) model of Traumatic Brain Injury (TBI) and were compared to both a Sham-operated and NaÔve control. Both (WT) (+/+) and (Het) (+/-) mice had robust microglia activation following CCI injuries. But surprisingly, Sham-operated (Het) (+/-) mice exhibited significant microglia activation as well, suggesting that the microglia in the Par1b (Het) (+/-) mice are hypersensitized to insults. Taken together, these results suggest microglia deficient of Par1 exhibit increased neuroinflammation and worsens injury outcomes.

We next sought to explore if negative behavioral and cellular outcomes following injury can be rescued by increasing Par1 activity. The pharmacotheraputic Metformin is known to stimulate the activity of LKB1, the major upstream activator of Par1. We examined if Metformin can be used post-injury to stimulate Par1 activity and improve negative TBI outcomes. Remarkably, administration of Metformin significantly improved learning and memory and nest building following injury. Furthermore, microglia in injured animals treated with Metformin show more ramified morphology, indicating reduced neuroinflammation. Together, these results suggest that restoring Par1 activity can rescue overactivation of microglia following injury, and improve negative behavioral responses.


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