Skip to main content
eScholarship
Open Access Publications from the University of California

UC San Diego

UC San Diego Electronic Theses and Dissertations bannerUC San Diego

Astrocyte-Specific Removal of PHLPP2 Alters Activation of Cell Survival Pathways Following LPS-Induced Inflammation

  • Author(s): Ohannesian, Shirag Hrand
  • Advisor(s): Purcell, Nicole H
  • et al.
No data is associated with this publication.
Abstract

Neurodegeneration is the progressive damage and deterioration of neurons often as a result of Alzheimer’s disease and Parkinson’s disease (Dauer and Przedborski, 2003), and the role of astrocytes in this process is becoming recognized. Neurodegenerative diseases have a positive correlation with other pro-inflammatory conditions such as diabetes mellitus, hypercholesterolemia, atherosclerosis, severe autism, and cardiovascular disease suggesting that chronic inflammation may play a role in the pathogenesis of neurodegenerative diseases (Exalto et al., 2012; Ledesma & Dotti, 2012; Emanuele et al., 2010). Astrocytes are crucial regulators of neuroinflammation. The extent of the inflammatory response is a delicate balance between cell survival and cell death. Astrocytic responses are context-dependent, and may aggravate inflammatory reactions and worsen tissue damage, or may suppress inflammation and increase tissue repair. Pleckstrin Homology domain and Leucine-rich repeat Protein Phosphatase (PHLPP) inhibits and terminates numerous important cell survival pathways through dephosphorylation of AGC Kinases such as Akt. Our laboratory has previously shown that removal of PHLPP1 in the brain is protective during ischemic damage (Chen et al., 2012). However, the role of PHLPP2 in the astrocytic response remains largely unknown. We used astrocyte-specific PHLPP2 knockout mice compared with global PHLPP2 knockout to study the role of PHLPP2 in astrocytes following a 4-hour lipopolysaccharide (LPS) treatment to induce inflammation. Changes in gene and protein expression of proteins involved in inflammation, NF-κB activation, apoptosis, mitogen-activated protein kinase stimulation, antioxidant, and autophagy levels were analyzed through Western blot and mRNA. We demonstrated that astrocyte-specific removal of PHLPP2 activates NF-κB, attenuates TNF-α and pro-apoptotic mediators, alters antioxidant activity, and increases activation of autophagy after 4 hours of LPS treatment. There seems to be more overall protection than harmful changes with astrocyte-specific removal of PHLPP2 in the pathways that we studied. However, we cannot conclude that those protective activations outweigh the harmful effects nor that removal of PHLPP2 in astrocytes will lead to better survival.

Main Content

This item is under embargo until April 1, 2023.