CSF1R — Colony Stimulating Factor 1 Receptor

Pathway Diagram

flowchart TD
    CSF1R["CSF1R"]
    style CSF1R fill:#006494,stroke:#4fc3f7,stroke-width:3px,color:#e0e0e0
    Als["Als"]
    CSF1R -->|"activates"| Als
    Blood_Brain_Barrier["Blood-Brain Barrier"]
    CSF1R -->|"activates"| Blood_Brain_Barrier
    microglia["microglia"]
    CSF1R -->|"regulates"| microglia
    MICROGLIA["MICROGLIA"]
    CSF1R -->|"inhibits"| MICROGLIA
    Leukemia["Leukemia"]
    CSF1R -->|"activates"| Leukemia
    Ms["Ms"]
    CSF1R -->|"activates"| Ms
    CSF1R -->|"inhibits"| Ms
    Depression["Depression"]
    CSF1R -->|"inhibits"| Depression
    PLX3397["PLX3397"]
    PLX3397 -->|"inhibits"| CSF1R
    dasatinib["dasatinib"]
    dasatinib -->|"inhibits"| CSF1R
    PLX5622["PLX5622"]
    PLX5622 -->|"inhibits"| CSF1R
    BDNF["BDNF"]
    BDNF -->|"associated with"| CSF1R
    AMYLOID["AMYLOID"]
    AMYLOID -->|"associated with"| CSF1R
    style Als fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
    style Blood_Brain_Barrier fill:#5d4400,stroke:#4fc3f7,color:#e0e0e0
    style microglia fill:#888,stroke:#4fc3f7,color:#e0e0e0
    style MICROGLIA fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
    style Leukemia fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
    style Ms fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
    style Depression fill:#ef5350,stroke:#4fc3f7,color:#e0e0e0
    style PLX3397 fill:#006494,stroke:#4fc3f7,color:#e0e0e0
    style dasatinib fill:#006494,stroke:#4fc3f7,color:#e0e0e0
    style PLX5622 fill:#006494,stroke:#4fc3f7,color:#e0e0e0
    style BDNF fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0
    style AMYLOID fill:#1b5e20,stroke:#4fc3f7,color:#e0e0e0

Introduction

Csf1R — Colony Stimulating Factor 1 Receptor is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.

Overview

CSF1R (Colony Stimulating Factor 1 Receptor, also known as CD115) is a receptor tyrosine kinase encoded on chromosome 5q32 that plays a pivotal role in the survival, proliferation, differentiation, and function of mononuclear phagocytes^{1CSF-1 receptor signaling in myeloid cells2014 · PMID 24825877Open reference}. CSF1R is the primary driver of microglial development and maintenance, making it a critical gene in neurodegenerative disease research. Heterozygous pathogenic variants in CSF1R cause adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP/HDSL), a hereditary progressive white matter disorder. The gene is catalogued as NCBI Gene ID 1436 and OMIM 164770.

Function

CSF1R Signaling Pathway

CSF1R is activated by three ligands: CSF1 (M-CSF), IL-34, and CSF1V (viral CSF1)^{2Function of CSF1 and IL-34 in microglia2018 · PMID 29666163Open reference}. Upon ligand binding, CSF1R undergoes:

1. Dimerization: Two CSF1R molecules pair in the membrane

2. Autophosphorylation: Intracellular tyrosine residues are phosphorylated

3. Docking site creation: Phospho-tyrosines recruit downstream signaling proteins

4. Signal transduction: Multiple pathways are activated

Downstream Signaling Pathways

• PI3K/AKT pathway: Cell survival, proliferation, metabolism

• MAPK/ERK pathway: Cell growth, differentiation

• STAT3 pathway: Transcriptional regulation, inflammation

• PLCγ pathway: Calcium signaling, cytoskeletal reorganization

• NF-κB pathway: Pro-inflammatory gene expression

Role in Microglia

CSF1R is essentially the master regulator of microglia^{3Fate mapping analysis reveals that adult microglia derive from primitive macrophages2010 · PMID 20966214Open reference}:

• Development: CSF1R signaling is absolutely required for microglial progenitor survival and proliferation during embryonic development

• Maintenance: Adult microglia depend on CSF1R signaling for homeostasis

• Activation: CSF1R modulates microglial activation states, influencing the neurotoxic vs. neuroprotective phenotype

• Repopulation: After depletion (e.g., from radiation), microglia repopulate from resident progenitors in a CSF1R-dependent manner

Brain Expression

• Microglia: Highest expression in brain; CSF1R is the defining marker of microglia

• Macrophages: Tissue-resident and infiltrating macrophages

• Osteoclasts: Bone-resorbing cells (in bone marrow)

• Placenta: Hofbauer cells (placental macrophages)

• Liver: Kupffer cells (liver macrophages)

Expression data is available from the Allen Human Brain Atlas.

Disease Associations

Adult-Onset Leukoencephalopathy with Spheroids and Pigmented Glia (ALSP)

ALSP (also known as Hereditary Diffuse Leukoencephalopathy with Spheroids, HDLS) is an autosomal dominant disorder caused by heterozygous pathogenic variants in CSF1R^{4Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids2012 · PMID 22197934Open reference}.

Clinical Features

• Age of onset: Typically 30-50 years (can range from 18-78)

• Progressive neurological decline:

  • Cognitive impairment (subcortical dementia, executive dysfunction)

  • Personality changes (apathy, disinhibition)

  • Psychiatric symptoms (depression, psychosis)

  • Motor symptoms (parkinsonism, gait disturbance, spasticity)

  • Seizures

• Neuroimaging:

  • Confluent white matter hyperintensities (T2/FLAIR)

  • Posterior predominance (occipital lobes)

  • Corpus callosum thinning

  • Cortical atrophy (later stages)

Pathophysiology

CSF1R mutations cause loss of function in the receptor tyrosine kinase^{5CSF1R-related leukoencephalopathy: clinical, radiologic, and pathologic features2018 · PMID 29669928Open reference}:

• ** Haploinsufficiency**: Mutant allele produces insufficient functional protein

• Dominant-negative effect: Mutant protein may interfere with wild-type signaling

• Microglial dysfunction: Impaired microglial survival, activation, and homeostasis

• White matter degeneration: Axonal spheroids, myelin loss, pigmented glia

Alzheimer’s Disease

CSF1R is a major therapeutic target in AD due to its role in microglial biology^{6TREM2 maintains microglial metabolic fitness in Alzheimer's disease2017 · PMID 28841419Open reference}:

• Microglial activation: CSF1R drives disease-associated microglia (DAM) formation

• Amyloid response: Microglia clear Aβ via CSF1R-dependent mechanisms

• Neuroinflammation: CSF1R signaling can be protective or detrimental depending on context

• Genetic risk: CSF1R variants may modify AD risk

Parkinson’s Disease

• Microglial activation: CSF1R mediates chronic neuroinflammation in PD

• Alpha-synuclein clearance: Microglial phagocytosis of α-synuclein

• Therapeutic targeting: CSF1R inhibitors being explored

Amyotrophic Lateral Sclerosis (ALS)

• Microglial heterogeneity: CSF1R+ microglia in ALS show disease-specific activation

• Neuroinflammation: Targeting CSF1R may modulate detrimental inflammation

• Therapeutic potential: CSF1R modulators in development

Multiple Sclerosis

• Demyelination: CSF1R signaling affects oligodendrocyte precursor cells

• Remyelination: Modulating microglia via CSF1R

• Therapeutic trials: CSF1R inhibitors in MS

Key Mutations

Most pathogenic variants cluster in the tyrosine kinase domain (exons 12-22), impairing enzymatic function^{7Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): overview of clinical features and CSF1R2020 · PMID 32719644Open reference}.

Diagnosis

Genetic Testing

• Targeted panel: CSF1R sequencing for leukoencephalopathy workup

• Whole exome sequencing: Used when phenotype suggests hereditary leukoencephalopathy

• Interpretation: Pathogenic/likely pathogenic variants confirm diagnosis

Neuroimaging

• MRI brain: T2/FLAIR hyperintensities in periventricular and deep white matter

• Diffusion tensor imaging: Reduced fractional anisotropy

• MRS: Elevated choline, decreased N-acetylaspartate

Cerebrospinal Fluid

• Routine analysis: Typically normal

• Neurofilament light chain (NfL): Often elevated (marker of axonal damage)

Treatment and Management

Current Approaches

No FDA-approved disease-modifying therapy exists for ALSP. Management includes^{8CSF1R-related leukoencephalopathy: long-term outcomes and treatment2022 · PMID 35115372Open reference}:

1. Symptomatic treatment:

   • Physical/occupational therapy

   • Cognitive rehabilitation

   • Psychiatric management

   • Anti-spasticity medications (baclofen, tizanidine)

2. Monitoring:

   • Regular MRI to track disease progression

   • Neuropsychological testing

   • Functional assessments

Emerging Therapies

CSF1R Agonists

• ** recombinant CSF1 (m-CSF)**: May enhance microglial function

• IL-34: Alternative ligand; potential therapeutic

• Small molecule agonists: In development

CSF1R Antagonists/Inhibitors

Paradoxically, CSF1R antagonists are being investigated for neurodegenerative diseases to modulate harmful neuroinflammation^{9Pharmacological inhibition of CSF1R by PLX3397 reduces microglial activation and disease progression in ALS mouse models2021 · PMID 34181967Open reference}:

Gene Therapy

• AAV-vector delivery: Express wild-type CSF1R

• CRISPR-based approaches: Correct pathogenic variants

Microglial Repopulation

• Bone marrow transplantation: Experimental approach to replace dysfunctional microglia

• CSF1R-independent pathways: Exploring alternative microglial engraftment

Key Publications

1. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nature Genetics, 2012. PMID: 22197934

2. CSF1R-related leukoencephalopathy: a major player in primary microgliopathies. Neurology, 2019. PMID: 30651363

3. Colony-stimulating factor 1 receptor-related disorder. Neurology Genetics, 2023.

4. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: clinical and neuropathological features. Brain, 2016. PMID: 26740088

5. CSF1R inhibitor therapy for microglia-mediated neurodegeneration. Nature Neuroscience, 2014. PMID: 25482915

6. Microglia in Alzheimer’s disease: adaptive or maladaptive?. Neuron, 2023.

7. CSF1R signaling in brain development and disease. Trends in Neurosciences, 2021.

8. Targeting microglia in neurodegenerative disease. Nature Reviews Neurology, 2020.

9. CSF1R mutations in ALSP: understanding genotype-phenotype correlations. Neurology, 2022.

10. Microglial replacement therapy: a new approach for neurodegenerative disease. Cell Stem Cell, 2023.

External Links

• NCBI Gene: https://www.ncbi.nlm.nih.gov/gene/1436

• Ensembl: https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000182578

• OMIM: https://omim.org/entry/164770

• UniProt: https://www.uniprot.org/uniprot/P07333

• Allen Human Brain Atlas: CSF1R expression

See Also

• alsp

• hdls

• neurons](/entities)

• csf1r-inhibitors-neurodegeneration](/therapeutics)

• Genes Index

• [Proteins Index

Background

The study of Csf1R — Colony Stimulating Factor 1 Receptor has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.

Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.

Brain Atlas Resources

• Allen Human Brain Atlas - CSF1R Expression](/datasets/allen-human-brain-atlas)

• Allen Cell Type Atlas - CSF1R

• BrainSpan - CSF1R Developmental Expression

• Allen Mouse Brain Atlas - CSF1R