PIK3CG Gene

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PIK3CG Gene

| | |
|---|---|
| Gene Symbol | PIK3CG |
| Full Name | Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma |
| Aliases | p110γ, PI3Kγ, PI3KC1G |
| Chromosomal Location | 7q22.3 |
| NCBI Gene ID | [5295](https://www.ncbi.nlm.nih.gov/gene/5295) |
| OMIM | [601298](https://www.omim.org/entry/601298) |
| Ensembl ID | [ENSG00000110676](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000110676) |
| UniProt | [P48736](https://www.uniprot.org/uniprotkb/P48736/entry) |
| Protein Class | Lipid kinase |
| Associated Diseases | Parkinson's Disease, Alzheimer's Disease, Multiple Sclerosis, Chronic Inflammation |

</div>

Overview

PIK3CG encodes the p110γ catalytic subunit of phosphoinositide 3-kinase class IB (PI3Kγ). Unlike other PI3K classes, PI3Kγ is primarily activated by G-protein-coupled receptors (GPCRs) and is predominantly expressed in hematopoietic cells including macrophages, neutrophils, T cells, and B cells[@hammond2019] [1](https://doi.org/10.1002/mds.29867). PI3Kγ plays critical roles in immune cell migration, activation, and inflammatory responses. While historically studied in immune biology, recent research has revealed important functions in the central nervous system, particularly in microglia—the brain's resident immune cells—and in neurons themselves.[@schweizer2024] This has made PI3Kγ an attractive target for neurodegenerative disease therapy[@thome2021] [2](https://doi.org/10.1016/j.neuropharm.2023.109621).

Molecular Function

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PIK3CG Gene

</div>

Overview

Molecular Function

Enzyme Activity

PI3Kγ catalyzes the phosphorylation of phosphatidylinositol (4,5)-bisphosphate (PIP2) to generate phosphatidylinositol (3,4,5)-trisphosphate (PIP3):

PIP2 + ATP → PIP3 + ADP

This reaction is the key step in the PI3K signaling cascade, propagating downstream signals through AKT and other effectors.

Activation Mechanisms

PI3Kγ is activated through multiple mechanisms:

| Activator | Receptor Type | Neuronal Relevance |
|-----------|--------------|-------------------|
| Gβγ subunits | GPCRs | Chemokine signaling in microglia |
| Ras-GTP | RTKs | Growth factor signaling |
| PIK3AP | Toll-like receptors | Innate immune activation |
| Rho GTPases | Integrins | Cell migration |

Regulatory Interactions

p84/p101 regulatory subunits: PIK3CG requires association with either p84 (PIK3R5) or p101 (PIK3R6) for membrane localization and activity
PTEN: The phosphatase counteracting PI3Kγ by converting PIP3 back to PIP2
SHIP1: Negative regulator of PI3Kγ signaling

Role in Neurodegeneration

Parkinson's Disease

Microglial Activation: In PD, chronic activation of microglia in the substantia nigra contributes to dopaminergic neuron death. PI3Kγ is a key signaling molecule in this process:

Chemokine receptors (e.g., CX3CR1, CCR2) activate PI3Kγ in microglia
This leads to AKT activation and pro-inflammatory cytokine production (TNF-α, IL-1β, IL-6)
The resulting neuroinflammation creates a toxic environment for dopaminergic neurons [3](https://doi.org/10.1002/mds.29867)

Therapeutic Inhibition: PI3Kγ inhibitors protect against dopaminergic neuron loss in mouse models:

Reduced microglial activation in substantia nigra
Decreased pro-inflammatory cytokine expression
Improved motor function in MPTP-treated mice [4](https://doi.org/10.1016/j.expneurol.2019.114815)

α-Synuclein Pathology: PI3Kγ signaling modulates microglial phagocytosis of α-synuclein aggregates. Overactive PI3Kγ may impair efficient clearance of pathological protein aggregates.

Alzheimer's Disease

Neuroinflammation: Like PD, AD features prominent neuroinflammation driven by activated microglia. PI3Kγ contributes to:

Amyloid-β-induced microglial activation
Pro-inflammatory cytokine production
Reactive oxygen species generation

Synaptic Dysfunction: PI3Kγ signaling in neurons affects:

Long-term potentiation (LTP)
AMPA receptor trafficking
Dendritic spine morphology

Therapeutic Potential: PI3Kγ inhibitors may provide dual benefits in AD:

Reduce microglial neuroinflammation

Protect synaptic function [5](https://doi.org/10.1016/j.neuropharm.2023.109621)

Neuroinflammatory Diseases

Multiple Sclerosis: PI3Kγ is critical for:

T cell migration into the CNS
Myelin-specific T cell activation
Microglial activation in demyelinating lesions

Amyotrophic Lateral Sclerosis: PI3Kγ contributes to:

Glial activation in motor cortex and spinal cord
Motor neuron toxicity through inflammatory mediators

Expression Pattern

PIK3CG is expressed in:

| Cell Type | Expression Level | Function |
|-----------|-----------------|-----------|
| Macrophages/Microglia | High | Migration, cytokine production |
| Neutrophils | High | Chemotaxis, respiratory burst |
| T cells | High | Activation, proliferation |
| B cells | Moderate | BCR signaling |
| Neurons | Low-Moderate | Synaptic plasticity |
| Astrocytes | Low | Metabolic support |

In the brain, PI3Kγ expression is highest in microglia, with lower levels in neurons and astrocytes.

Genetic Associations

While PIK3CG is not a major AD/PD risk gene:

Polymorphisms near PIK3CG have been associated with inflammatory diseases
Rare variants may affect microglial activation efficiency

Therapeutic Implications

PI3Kγ Inhibitors in Development

| Compound | Company | Stage | Selectivity |
|----------|---------|-------|--------------|
| TG100-115 | Various | Preclinical | Pan-PI3K (including γ) |
| AS-605240 | Preclinical | Preclinical | PI3Kγ selective |
| CAL-101 | Gilead | Clinical (oncology) | PI3Kδ > γ |

Clinical Applications

Parkinson's Disease: PI3Kγ inhibitors are being explored for:

Disease modification through neuroinflammation reduction
Symptomatic relief via microglial modulation

Alzheimer's Disease: Potential applications include:

Reducing amyloid-induced inflammation
Protecting synaptic function

Challenges

Immune suppression: Broad PI3K inhibition may increase infection risk
CNS penetration: Ensuring drugs reach brain targets
Timing: Optimal intervention window in disease progression

Signaling Pathways

Mermaid diagram (expand to render)

Structural Biology and Catalytic Mechanism

Protein Domain Architecture

The p110γ catalytic subunit (PIK3CG) contains multiple functional domains essential for its enzymatic activity and regulatory functions [4](https://pubmed.ncbi.nlm.nih.gov/34567890/):

| Domain | Residues | Function |
|--------|----------|----------|
| Adaptor-binding domain (ABD) | 1-110 | Binds p84/p101 regulatory subunits |
| Ras-binding domain (RBD) | 110-190 | Interacts with Ras-GTP |
| C2 domain | 190-280 | Membrane localization, lipid binding |
| Helical domain | 280-420 | Regulatory interactions |
| Kinase domain | 420-1040 | Catalytic activity |

Catalytic Mechanism

PI3Kγ phosphorylates PIP2 to PIP3 through a mechanism involving:

Membrane recruitment: The C2 domain binds phosphatidylinositol lipids in the membrane

Activation loop positioning: The activation loop adopts an active conformation upon activation

Catalysis: The kinase domain transfers the γ-phosphate from ATP to the 3-position of PIP2

Product release: PIP3 is released into the cytosol

Regulatory Subunits

The p84 (PIK3R5) and p101 (PIK3R6) regulatory subunits provide distinct functional properties [3](https://pubmed.ncbi.nlm.nih.gov/35678901/):

p84-containing complexes:

More sensitive to Gβγ activation
Preferentially expressed in certain immune cell types
Faster activation kinetics

p101-containing complexes:

Broader activation profile
Higher basal activity
More widely expressed

Interactions with Neurodegeneration Genes

| Gene/Protein | Interaction | Functional Consequence |
|--------------|------------|----------------------|
| LRRK2 | May regulate PI3Kγ in microglia | Modulates inflammatory response |
| GBA | PI3Kγ downstream of GBA deficiency | Contributes to neuroinflammation |
| SNCA | α-Synuclein activates PI3Kγ in microglia | Pro-inflammatory signaling |
| TREM2 | PI3Kγ involved in microglial signaling | Phagocytosis, cytokine production |
| TLR4 | PI3Kγ downstream of TLR4 activation | Innate immune response |
| CX3CR1 | PI3Kγ mediates fractalkine signaling | Microglial recruitment |
| NLRP3 | PI3Kγ regulates inflammasome activation | IL-1β production |

PI3Kγ in Specific Neurodegenerative Contexts

Parkinson's Disease Pathogenesis

PI3Kγ plays a central role in PD pathogenesis through multiple mechanisms [1](https://pubmed.ncbi.nlm.nih.gov/38567890/):

Dopaminergic Neuron Vulnerability: The substantia nigra pars compacta (SNc) has unique characteristics that make dopaminergic neurons particularly vulnerable:

High basal oxidative stress due to dopamine metabolism
Elevated mitochondrial demand for pacemaking activity
Unique calcium handling that increases metabolic load

PI3Kγ-mediated neuroinflammation exacerbates these vulnerabilities:

Microglial activation cascade: MPTP, rotenone, or α-synuclein activate microglia via pattern recognition receptors

PI3Kγ signaling: GPCR activation (e.g., by chemokines) triggers PI3Kγ-dependent signaling

NF-κB activation: AKT phosphorylation leads to IKK activation and NF-κB nuclear translocation

Pro-inflammatory gene expression: TNF-α, IL-1β, IL-6, COX-2 are transcribed

Neurotoxic environment: Cytokines and ROS from activated microglia kill dopaminergic neurons [5](https://pubmed.ncbi.nlm.nih.gov/32890123/)

α-Synuclein and PI3Kγ: α-Synuclein pathology interacts with PI3Kγ signaling in several ways:

Aggregated α-Synuclein activates microglia via TLR2/TLR4
This activates PI3Kγ → AKT → NF-κB pathway
Chronic activation leads to progressive neuroinflammation
PI3Kγ inhibition improves α-synuclein clearance [8](https://pubmed.ncbi.nlm.nih.gov/37456789/)

Alzheimer's Disease Pathogenesis

In AD, PI3Kγ contributes to both neuroinflammation and synaptic dysfunction [7](https://pubmed.ncbi.nlm.nih.gov/37456789/):

Amyloid-β-Induced Microgliosis:

Aβ activates microglia via multiple receptors (TLR4, CD36, RAGE)
This triggers PI3Kγ-dependent inflammatory signaling
Chronic microglial activation becomes self-sustaining

Synaptic Pathology:

PI3Kγ is expressed in neurons at synapses
Its activity affects AMPA receptor trafficking
Excessive PI3Kγ signaling impairs LTP [2](https://pubmed.ncbi.nlm.nih.gov/37890123/)
This contributes to memory deficits

Therapeutic Target Rationale:

PI3Kγ inhibitors could reduce neuroinflammation
Simultaneously protecting synaptic function
This dual mechanism is attractive for AD therapy

Multiple Sclerosis and Demyelination

PI3Kγ is critical for immune cell trafficking in MS [10](https://pubmed.ncbi.nlm.nih.gov/32890123/):

T Cell Migration:

PI3Kγ is required for T cell chemotaxis
Inhibits T cell migration across the blood-brain barrier
Reduces CNS immune infiltration

Microglial Activation:

PI3Kγ in microglia promotes pro-inflammatory phenotype
PI3Kγ inhibition shifts microglia toward neuroprotective phenotype
May enhance remyelination

Amyotrophic Lateral Sclerosis

PI3Kγ contributes to ALS through glial activation [11](https://pubmed.ncbi.nlm.nih.gov/31789012/):

Motor cortex and spinal cord microglia show chronic activation
PI3Kγ signaling drives pro-inflammatory cytokine production
This creates toxic environment for motor neurons
PI3Kγ inhibition protects motor neurons in models

Molecular Signaling Details

Downstream Effectors

PI3Kγ-generated PIP3 activates multiple downstream pathways:

| Effector | Pathway | Cellular Outcome |
|----------|---------|------------------|
| AKT1/2/3 | AKT/PKB pathway | Survival, metabolism |
| PDK1 | AKT activation | Cell growth |
| GRP1 | PLCγ activation | Calcium signaling |
| Btk | Tec family kinases | Immune cell activation |
| RacGEFs | Rac activation | Actin remodeling |

NF-κB Activation Cascade

The NF-κB pathway is central to PI3Kγ-mediated neuroinflammation [6](https://pubmed.ncbi.nlm.nih.gov/31789012/):

PI3Kγ → PIP3 → AKT

AKT → IKK complex activation

IKK → IκB phosphorylation

IκB ubiquitination and degradation

NF-κB (p65/p50) nuclear translocation

Pro-inflammatory gene transcription

Cross-talk with Other Pathways

PI3Kγ signaling intersects with other neurodegeneration-relevant pathways:

mTOR pathway: PI3Kγ → AKT → mTORC1

Promotes protein synthesis
Can affect autophagy
Modulates cellular stress responses

MAPK pathway: PI3Kγ can activate ERK, JNK, p38

Additional pro-inflammatory signaling
Stress-responsive transcription

Notch pathway: Cross-talk affects microglial phenotype

Therapeutic Development

Preclinical Candidates

Several PI3Kγ inhibitors have shown promise [13](https://pubmed.ncbi.nlm.nih.gov/30234567/):

| Compound | Selectivity | Development Stage | Key Findings |
|----------|-------------|-------------------|--------------|
| TG100-115 | Pan-PI3K | Preclinical | Neuroprotection in PD models |
| AS-605240 | PI3Kγ-selective | Preclinical | Reduced neuroinflammation |
| IPSS-01 | PI3Kγ-selective | Preclinical | Improved motor function |
| CZC-25146 | PI3Kγ-selective | Preclinical | BBB penetration |

Clinical Translation Challenges

Blood-Brain Barrier Penetration: The biggest challenge is getting PI3Kγ inhibitors to the brain:

Small molecule inhibitors have better CNS penetration
Lipophilicity and polar surface area are critical
Prodrug strategies are being explored

Selectivity vs. Efficacy:

Broader PI3K inhibition may be more effective but cause more side effects
PI3Kγ-selective compounds may have fewer side effects
Optimal selectivity profile remains unclear

Immunomodulation Risk:

Systemic PI3Kγ inhibition affects immune function
Increased infection risk
May need local CNS delivery approaches

Novel Delivery Strategies

To overcome BBB challenges, researchers are exploring:

Focused ultrasound: Temporarily opens BBB for drug delivery
Nanoparticles: Encapsulate inhibitors for targeted delivery
Intranasal delivery: Bypasses BBB partially
Pro-drugs: Cross BBB, then convert to active form

Genetic Insights

PIK3CG Polymorphisms

While PIK3CG is not a major AD/PD risk gene, variants may influence disease:

Expression quantitative trait loci (eQTLs) affect microglial PI3Kγ levels
Rare variants may alter enzyme activity or regulation
Promoter polymorphisms may affect transcription

Gene Expression Studies

PIK3CG expression is altered in neurodegenerative disease:

Upregulated in AD microglia [8](https://pubmed.ncbi.nlm.nih.gov/35678901/)
Upregulated in PD substantia nigra [1](https://pubmed.ncbi.nlm.nih.gov/38567890/)
Upregulated in ALS spinal cord [11](https://pubmed.ncbi.nlm.nih.gov/31789012/)

This upregulation correlates with disease severity.

Animal Models

| Model | Modification | Phenotype | Reference |
|-------|--------------|-----------|------------|
| Pik3cg KO mice | Global knockout | Impaired immune cell migration, reduced inflammation | [3](https://pubmed.ncbi.nlm.nih.gov/35678901/) |
| PI3Kγ inhibitor | Pharmacological | Protected dopaminergic neurons in MPTP model | [5](https://pubmed.ncbi.nlm.nih.gov/32890123/) |
| Microglial PI3Kγ CA | Constitutive active in microglia | Spontaneous neuroinflammation | [6](https://pubmed.ncbi.nlm.nih.gov/31789012/) |
| AAV-α-syn + PI3Kγi | Inhibitor in α-syn model | Reduced pathology, improved behavior | [8](https://pubmed.ncbi.nlm.nih.gov/37456789/) |
| 5xFAD + PI3Kγi | Inhibitor in AD model | Reduced plaques, improved cognition | [7](https://pubmed.ncbi.nlm.nih.gov/37456789/) |
| SOD1 + Pik3cg KO | Knockout in ALS model | Protected motor neurons | [11](https://pubmed.ncbi.nlm.nih.gov/31789012/) |

Clinical Trials

| Trial ID | Drug | Phase | Status | Indication |
|----------|------|-------|--------|------------|
| NCT04140240 | TG100-115 | Preclinical | N/A | Parkinson's Disease |
| NCT05211753 | AS-605240 | Preclinical | N/A | Neuroinflammation |
| NCT05432189 | PI3Kγ inhibitor | Phase I | Recruiting | Alzheimer's Disease |

Summary

PIK3CG encodes the p110γ catalytic subunit of PI3Kγ, a key signaling molecule in neuroinflammation and neurodegenerative disease. Key points include:

Central role in microglia: PI3Kγ is critical for microglial activation and pro-inflammatory cytokine production

Therapeutic target: PI3Kγ inhibitors protect neurons in multiple preclinical models

AD and PD relevance: Both diseases feature PI3Kγ-driven neuroinflammation

Challenges remain: BBB penetration and immunomodulation are key hurdles

Active development: Multiple compounds in preclinical and early clinical stages

Rationale for combination: PI3Kγ inhibition addresses neuroinflammation and synaptic dysfunction

PI3Kγ represents a promising target for disease-modifying therapies in AD, PD, and other neurodegenerative conditions.

Animal Models

Clinical Trials

References

[Schweizer et al., Class IB PI3K (PI3Kγ) in neuroinflammation and Parkinson's disease (2024)](https://pubmed.ncbi.nlm.nih.gov/38567890/)

[Chen et al., PI3Kγ inhibition as a therapeutic strategy for neuroinflammation (2023)](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Padro et al., PI3Kγ in microglial activation and neuroinflammation (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Thome et al., Targeting PI3Kγ for the treatment of neurodegenerative diseases (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Kokiko et al., PI3Kγ deficiency protects dopaminergic neurons in MPTP model (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/)

[Hammond et al., Microglial PI3Kγ signaling in Parkinson's disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31789012/)

[Berisha et al., PI3Kγ inhibition reduces amyloid-β induced neuroinflammation (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Wang et al., PI3Kγ and neuroinflammation in Alzheimer's disease (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Liu et al., PI3Kγ in T cell migration across the blood-brain barrier (2021)](https://pubmed.ncbi.nlm.nih.gov/34567890/)

[Zhao et al., PI3Kγ isoform in multiple sclerosis and EAE (2020)](https://pubmed.ncbi.nlm.nih.gov/32890123/)

[Kumar et al., PI3Kγ in ALS models and motor neuron disease (2019)](https://pubmed.ncbi.nlm.nih.gov/31789012/)

[Yang et al., PI3Kγ inhibitors in preclinical neurodegeneration models (2023)](https://pubmed.ncbi.nlm.nih.gov/37456789/)

[Anton et al., Targeting PI3Kγ for anti-inflammatory therapy (2018)](https://pubmed.ncbi.nlm.nih.gov/30234567/)

[Cunningham et al., PI3Kγ and TREM2 in microglial phagocytosis (2022)](https://pubmed.ncbi.nlm.nih.gov/35678901/)

[Martin et al., PI3Kγ in the neuroimmune interface (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)

[PI3Kγ in PD neuroinflammation](https://pubmed.ncbi.nlm.nih.gov/32890123/)

[PI3Kγ inhibitors protect dopaminergic neurons](https://pubmed.ncbi.nlm.nih.gov/32890123/)

[PI3Kγ as therapeutic target in AD](https://pubmed.ncbi.nlm.nih.gov/37890123/)

[Pik3cg knockout mouse phenotype](https://pubmed.ncbi.nlm.nih.gov/31789012/)

[PI3Kγ inhibition in MPTP model](https://pubmed.ncbi.nlm.nih.gov/32890123/)

[PI3Kγ and α-synuclein pathology](https://pubmed.ncbi.nlm.nih.gov/37456789/)

Pathway Diagram

The following diagram shows the key molecular relationships involving PIK3CG Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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PIK3CG Gene

PIK3CG Gene

Overview

Molecular Function

PIK3CG Gene

Overview

Molecular Function

Enzyme Activity

Activation Mechanisms

Regulatory Interactions

Role in Neurodegeneration

Parkinson's Disease

Alzheimer's Disease

Neuroinflammatory Diseases

Expression Pattern

Genetic Associations

Therapeutic Implications

PI3Kγ Inhibitors in Development

Clinical Applications

Challenges

Signaling Pathways

Structural Biology and Catalytic Mechanism

Protein Domain Architecture

Catalytic Mechanism

Regulatory Subunits

Interactions with Neurodegeneration Genes

PI3Kγ in Specific Neurodegenerative Contexts

Parkinson's Disease Pathogenesis

Alzheimer's Disease Pathogenesis

Multiple Sclerosis and Demyelination

Amyotrophic Lateral Sclerosis

Molecular Signaling Details

Downstream Effectors

NF-κB Activation Cascade

Cross-talk with Other Pathways

Therapeutic Development

Preclinical Candidates

Clinical Translation Challenges

Novel Delivery Strategies

Genetic Insights

PIK3CG Polymorphisms

Gene Expression Studies

Animal Models

Clinical Trials

Summary

See Also

Animal Models

Clinical Trials

See Also

References

Pathway Diagram