Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph

ABSTRACTRecent Genome Wide Association Studies (GWAS) have identified novel rare coding variants in immune genes associated with late onset AD (LOAD). Amongst these, a polymorphism in Phospholipase C-gamma 2 (PLCG2) P522R, has been reported to be protective against LOAD. PLC enzymes are key elements in signal transmission networks and are potentially druggable targets. PLCG2 is highly expressed in the hematopoietic system. Hypermorphic mutations in PLCG2 in humans have been reported to cause autoinflammation and immune disorders, suggesting a key role for this enzyme in the regulation of immune cell function.We confirmed that PLCG2 expression is restricted primarily to microglia in both the healthy and AD brain. Functional analysis of the P522R variant in heterologous systems demonstrated a small hypermorphic effect of the mutation on enzyme function. PLCγ2 is therefore a potential target for modulating microglia function in AD, and a small molecule drug that weakly activates PLCγ2 may be one potential therapeutic approach.SUMMARYThe PLCG2 P522R variant is protective against Alzheimer’s disease (AD). We show that PLCG2 is expressed in CNS-resident myeloid cells, and the P522R polymorphism weakly activates enzyme function. These data suggest that activation of PLCG2 and not inhibition could be therapeutically beneficial in AD.

Download Full-text

Correction for Kim et al., Prediction of Alzheimer’s disease-specific phospholipase c gamma-1 SNV by deep learning-based approach for high-throughput screening

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2101727118 ◽

2021 ◽

Vol 118 (9) ◽

pp. e2101727118

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Deep Learning ◽

Phospholipase C ◽

High Throughput ◽

High Throughput Screening ◽

Phospholipase C Gamma ◽

Disease Specific

Download Full-text

Prediction of Alzheimer’s disease-specific phospholipase c gamma-1 SNV by deep learning-based approach for high-throughput screening

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2011250118 ◽

2021 ◽

Vol 118 (3) ◽

pp. e2011250118

Author(s):

Sung-Hyun Kim ◽

Sumin Yang ◽

Key-Hwan Lim ◽

Euiseng Ko ◽

Hyun-Jun Jang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Deep Learning ◽

Mouse Model ◽

Phospholipase C ◽

Messenger Rna ◽

Single Nucleotide ◽

Exon Splicing ◽

Phospholipase C Gamma ◽

Ad Mouse Model

Exon splicing triggered by unpredicted genetic mutation can cause translational variations in neurodegenerative disorders. In this study, we discover Alzheimer’s disease (AD)-specific single-nucleotide variants (SNVs) and abnormal exon splicing of phospholipase c gamma-1 (PLCγ1) gene, using genome-wide association study (GWAS) and a deep learning-based exon splicing prediction tool. GWAS revealed that the identified single-nucleotide variations were mainly distributed in the H3K27ac-enriched region of PLCγ1 gene body during brain development in an AD mouse model. A deep learning analysis, trained with human genome sequences, predicted 14 splicing sites in human PLCγ1 gene, and one of these completely matched with an SNV in exon 27 of PLCγ1 gene in an AD mouse model. In particular, the SNV in exon 27 of PLCγ1 gene is associated with abnormal splicing during messenger RNA maturation. Taken together, our findings suggest that this approach, which combines in silico and deep learning-based analyses, has potential for identifying the clinical utility of critical SNVs in AD prediction.

Download Full-text

Phosphoinositide hydrolysis, Gαq, phospholipase C, and protein kinase C in post mortem human brain: Effects of post mortem interval, subject age, and alzheimer's disease

Neuroscience ◽

10.1016/0306-4522(95)00220-d ◽

1995 ◽

Vol 69 (1) ◽

pp. 125-138 ◽

Cited By ~ 49

Author(s):

A.F. Greenwood ◽

R.E. Powers ◽

R.S. Jope

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Protein Kinase C ◽

Protein Kinase ◽

Human Brain ◽

Phospholipase C ◽

Phosphoinositide Hydrolysis ◽

Post Mortem ◽

Post Mortem Interval ◽

Kinase C

Download Full-text

The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions

Molecular Neurodegeneration ◽

10.1186/s13024-020-00402-7 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Mari Takalo ◽

Rebekka Wittrahm ◽

Benedikt Wefers ◽

Samira Parhizkar ◽

Kimmo Jokivarsi ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Immune Cell ◽

Therapeutic Option ◽

Immune Functions ◽

Disease Etiology ◽

Cell Functions ◽

Bv2 Microglia ◽

Brain Mrna ◽

Protective Variant

Abstract Background Microglia-specific genetic variants are enriched in several neurodegenerative diseases, including Alzheimer’s disease (AD), implicating a central role for alterations of the innate immune system in the disease etiology. A rare coding variant in the PLCG2 gene (rs72824905, p.P522R) expressed in myeloid lineage cells was recently identified and shown to reduce the risk for AD. Methods To assess the role of the protective variant in the context of immune cell functions, we generated a Plcγ2-P522R knock-in (KI) mouse model using CRISPR/Cas9 gene editing. Results Functional analyses of macrophages derived from homozygous KI mice and wild type (WT) littermates revealed that the P522R variant potentiates the primary function of Plcγ2 as a Pip2-metabolizing enzyme. This was associated with improved survival and increased acute inflammatory response of the KI macrophages. Enhanced phagocytosis was observed in mouse BV2 microglia-like cells overexpressing human PLCγ2-P522R, but not in PLCγ2-WT expressing cells. Immunohistochemical analyses did not reveal changes in the number or morphology of microglia in the cortex of Plcγ2-P522R KI mice. However, the brain mRNA signature together with microglia-related PET imaging suggested enhanced microglial functions in Plcγ2-P522R KI mice. Conclusion The AD-associated protective Plcγ2-P522R variant promotes protective functions associated with TREM2 signaling. Our findings provide further support for the idea that pharmacological modulation of microglia via TREM2-PLCγ2 pathway-dependent stimulation may be a novel therapeutic option for the treatment of AD.

Download Full-text