Phosphoinositides: Roles in the Development of Microglial-Mediated Neuroinflammation and Neurodegeneration

Abstract

Microglia are increasingly recognized as vital players in the pathology of a variety of neurodegenerative conditions including Alzheimer's (AD) and Parkinson's (PD) disease. While microglia have a protective role in the brain, their dysfunction can lead to neuroinflammation and contributes to disease progression. Also, a growing body of literature highlights the seven phosphoinositides, or PIPs, as key players in the regulation of microglial-mediated neuroinflammation. These small signaling lipids are phosphorylated derivates of phosphatidylinositol, are enriched in the brain, and have well-established roles in both homeostasis and disease.Disrupted PIP levels and signaling has been detected in a variety of dementias. Moreover, many known AD disease modifiers identified via genetic studies are expressed in microglia and are involved in phospholipid metabolism. One of these, the enzyme PLCγ2 that hydrolyzes the PIP species PI(4,5)P₂, displays altered expression in AD and PD and is currently being investigated as a potential therapeutic target.Perhaps unsurprisingly, neurodegenerative conditions exhibiting PIP dyshomeostasis also tend to show alterations in aspects of microglial function regulated by these lipids. In particular, phosphoinositides regulate the activities of proteins and enzymes required for endocytosis, toll-like receptor signaling, purinergic signaling, chemotaxis, and migration, all of which are affected in a variety of neurodegenerative conditions. These functions are crucial to allow microglia to adequately survey the brain and respond appropriately to invading pathogens and other abnormalities, including misfolded proteins. AD and PD therapies are being developed to target many of the above pathways, and although not yet investigated, simultaneous PIP manipulation might enhance the beneficial effects observed. Currently, only limited therapeutics are available for dementia, and although these show some benefits for symptom severity and progression, they are far from curative. Given the importance of microglia and PIPs in dementia development, this review summarizes current research and asks whether we can exploit this information to design more targeted, or perhaps combined, dementia therapeutics. More work is needed to fully characterize the pathways discussed in this review, but given the strength of the current literature, insights in this area could be invaluable for the future of neurodegenerative disease research.

Keywords: Alzheimer’s disease; Parkinson’s disease; chemotaxis; microglia; neurodegeneration; neuroinflammation; phagocytosis; phosphoinositols.

Figure 1

Structure, metabolism, and location of phosphatidylinositides (PIPs) within mammalian cells. (A) Structures of phosphatidylinositol (PI) and it is seven phosphoinositide (PIP) derivatives, generated by phosphorylation of the inositol ring at positions 3, 4 or 5. PI consists of diaglycerol (DAG, blue) bound to a D-myo-inositol ring (yellow) via a phosphodiester linkage (green). O, oxygen; H, hydrogen; P, phosphate; R, non-polar fatty acid tails. (B) Metabolic pathways regulating the interconversion of PIP species. Lipid kinases (red) phosphorylate the inositol ring at points 3, 4, or 5 to generated more phosphorylated PIPs while lipid phosphatases remove phosphate groups. MTM1, myotubularin1; MTMR, myotubularin-related protein; FIG4, Factor-Induced Gene 4; PTEN, phosphatase and tensin homolog; OCRL, inositol phosphatase 5-phosphatase; SYNJ1, synaptojanin 1; INPP5D, Src homology 2 (SH2) domain containing inositol polyphosphatase 5-phosphatase 1. (C) Primary locations of the different PIPs within the cell are shown by the colored stars. CIE, clathrin independent endocytosis; CIV, clathrin independent endocytic vesicle, CE, clathrin dependent endocytosis; EE, early endosome; RE, recycling endosome; SV, secretory vesicle; GA, golgi apparatus; ER, endoplasmic reticulum; MVB/LE, multi-vesicular body/late endosome; LYSO, lysosome.

Figure 2

Roles of PI(4,5)P₂ in early phagocytosis. (A) When a target is detected by a phagocytic cell PI(4)P is converted to PI(4,5)P₂by PIP5K. PIP5K associates with the plasma membrane along its positively charged surface. PI(4,5)P₂ mediates linkage of actin networks (red) to integral plasmalemmal proteins through intermediary ezrin, radixin, and moesin (ERM) proteins. (B) When the phagosome sealing begins depletion of PI(4,5)P₂ from the base of the cup leads to the removal of actin filaments. PI(4,5)P₂ is converted by kinases (PI3K), phosphatases (OCRL), and phospholipases (PLCγ). This allows the movement of the closed vacuole into the cell.

Figure 3

Functional role of phosphoinositides in cell migration. The binding of a chemoattractant to G-protein coupled receptors (e.g., P2Y12R) in the cell membrane releases the Gα heterodimer from the heterotrimeric Gα proteins. Dissociated Gα proteins stimulate PI(3,4,5)P₃ production from PI(4,5)P₂ via phosphoinositide 3-kinase (PI3K) and lead to membrane translocation of PI(3,4,5)P₃-binding actin-binding proteins (ABPs) such as myosin. This allows remodeling of the actin cytoskeleton at the leading edge, which is required for the formation of novel cell protrusions. Away from the leading edge PI(3,4,5)P₃ is converted back to PI(4,5)P₂ via phosphatase and tensin homolog (PTEN). PI(4,5)P₂ then inhibits actin assembly by binding capping proteins.