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.

Identification of Hub Genes and Immune Cell Infiltration Characteristics in Alzheimer’s Disease

“…Alzheimer's disease (AD) is a degenerative disease of the central nervous system that occurs in old age and pre-old age and is characterized by progressive cognitive dysfunction and behavioral impairment [ 1 , 2 ]. It is the most common type of dementia and one of the most common chronic diseases in old age [ 3 ], accounting for about 50% to 70% of dementia in old age [ 4 , 5 ]. While the exact cause of AD has not been elucidated, studies have found that AD is the result of a combination of genes, lifestyle, and environmental factors, caused in part by specific genetic changes [ 6 – 9 ].…”

Differential Effects of Posttranslational Modifications on the Membrane Interaction of Huntingtin Protein

“…The significance of the finding is underscored by the pivotal role PI45P2 plays in the nervous system, particularly in regulating various facets of the synaptic vesicle cycle. Supporting this, disruptions in phosphoinositides levels and signaling have been identified in numerous dementias 54 . Notably, both Alzheimer's Disease (AD) and Parkinson's Disease (PD) manifest alterations in the expression of phosphoinositide conversion enzymes, pinpointing these enzymes as promising therapeutic targets 55,56 .…”

The rational design of ARUK2007145, a dual inhibitor of the α and γ isoforms of the lipid kinase phosphatidylinositol 5-phosphate 4-kinase (PI5P4K)

“…The relative PI5P4Kα activity of 6 could be increased by methylation of the pyridyl 3-position (10) more effectively than by addition of OMe (11), or F ( 12) at the same position, or by chlorination at the pyridyl 2-position (13; Table 2). A range of small substituents was also trialled on template 6 and these were generally well tolerated (see [14][15][16][17]. Compound 17 was a useful lead from this set with a good balance of activity at PI5P4Kα and γ+ as well as one of the lower X log Ps in this series.…”

“…The promiscuity of the phosphoinositides in cellular signalling pathways has implications for disease as enzyme dysfunction or misregulation may be causative in various developmental disorders, inflammation and infection. [13][14][15][16] As oncology targets, PI5P4Ks have become increasingly associated with a number of diseases. 17 Interestingly the involvement of PI5P4Kα alone has been documented in glioblastoma, acute myeloid leukemia (AML) and prostate cancer [18][19][20][21] but other examples suggest that there may be a combinatorial role for the PI5P4Ks.…”