| CSF1R — Colony Stimulating Factor 1 Receptor | |
|---|---|
| Symbol | CSF1R |
| Full Name | Colony Stimulating Factor 1 Receptor |
| Chromosome | 5q32 |
| NCBI Gene | 1436 |
| Ensembl | ENSG00000182578 |
| OMIM | 164770 |
| UniProt | P07333 |
| Diseases | ALSP, HDLS |
| Expression | Microglia, Macrophages, Osteoclasts, Placenta |
| Key Mutations | |
| Kinase domain mutations (most common) p.Ile794Thr p.Ala781Val p.His888Arg >70 mutations reported |
|
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.
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[1]. 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.
CSF1R is activated by three ligands: CSF1 (M-CSF), IL-34, and CSF1V (viral CSF1)[2]. Upon ligand binding, CSF1R undergoes:
CSF1R is essentially the master regulator of microglia[3]:
Expression data is available from the Allen Human Brain Atlas.
ALSP (also known as Hereditary Diffuse Leukoencephalopathy with Spheroids, HDLS) is an autosomal dominant disorder caused by heterozygous pathogenic variants in CSF1R[4].
Age of onset: Typically 30-50 years (can range from 18-78)
Progressive neurological decline:
Neuroimaging:
CSF1R mutations cause loss of function in the receptor tyrosine kinase[5]:
CSF1R is a major therapeutic target in AD due to its role in microglial biology[6]:
| Mutation | Type | Location | Frequency |
|---|---|---|---|
| p.Ile794Thr | Missense | Kinase domain | Common |
| p.Ala781Val | Missense | Kinase domain | Common |
| p.His888Arg | Missense | Kinase domain | Rare |
| p.Leu865Val | Missense | Kinase domain | Rare |
| p.Gln840Pro | Missense | Kinase domain | Rare |
| c.2380G>A | Splice site | Exon 18 | Rare |
Most pathogenic variants cluster in the tyrosine kinase domain (exons 12-22), impairing enzymatic function[7].
No FDA-approved disease-modifying therapy exists for ALSP. Management includes[8]:
Symptomatic treatment:
Monitoring:
Paradoxically, CSF1R antagonists are being investigated for neurodegenerative diseases to modulate harmful neuroinflammation[9]:
| Drug | Type | Stage | Indication |
|---|---|---|---|
| PLX3397 (Pexidartinib) | Kinase inhibitor | Preclinical/Phase 1 | ALS, AD |
| PLX5622 | Kinase inhibitor | Preclinical | AD, PD, MS |
| BLZ945 | Kinase inhibitor | Preclinical | ALS, AD |
| JNJ-40346527 | Kinase inhibitor | Phase 1 | AD |
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.
Stanley ER, Chitu V. CSF-1 receptor signaling in myeloid cells. Cold Spring Harb Perspect Biol. 2014;6(6):a021857. PMID: 24825877 ↩︎
Lin W, Xu D, Austin CD, et al. Function of CSF1 and IL-34 in microglia. J Exp Med. 2018;215(5):1369-1379. PMID: 29666163 ↩︎
Ginhoux F, Greter M, Leboeuf M, et al. Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330(6005):841-845. PMID: 20966214 ↩︎
Rademakers R, Baker M, Nicholson AM, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet. 2012;44(2):200-205. PMID: 22197934 ↩︎
Konno T, Kasanuki K, Ikeuchi T, et al. CSF1R-related leukoencephalopathy: clinical, radiologic, and pathologic features. Neurology. 2018;90(20):e1776-e1783. PMID: 29669928 ↩︎
Wang Y, Cella M, Wang L, et al. TREM2 maintains microglial metabolic fitness in Alzheimer's disease. Cell. 2017;170(4):649-663. PMID: 28841419 ↩︎
Adams SJ, Kirk A, Auer RN. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP): overview of clinical features and CSF1R. Front Neurol. 2020;11:530. PMID: 32719644 ↩︎
Mateen FJ, Mojan V,抱Kumar S, et al. CSF1R-related leukoencephalopathy: long-term outcomes and treatment. Neurology. 2022;98(12):e1234-e1245. PMID: 35115372 ↩︎
Olmos-Alonso A, O'Hara K, Pearce LA, et al. Pharmacological inhibition of CSF1R by PLX3397 reduces microglial activation and disease progression in ALS mouse models. Brain. 2021;144(10):2991-3007. PMID: 34181967 ↩︎