CSF1R-related leukoencephalopathy: experimental models and potential for treatment

Area of Science:

• Neuroscience
• Genetics
• Pathology

Background:

• Mutations in the CSF1R gene are linked to microglial deficiency and CSF1R-related leukoencephalopathy (CRL), a severe neurodegenerative disease.
• Animal models (mice, rats, zebrafish, chicken) with Csf1r mutations mimic aspects of human microglial deficiency.

Purpose of the Study:

• To review the genetic basis of CRL and variable penetrance.
• To assess experimental models for developing therapeutic strategies for CRL.

Main Methods:

• Generation of dominant and recessive Csf1r mutations in various animal models.
• Analysis of the impact of Csf1r mutations on brain development and neuropathology.
• Evaluation of animal models for recapitulating human CRL symptoms and for therapeutic testing.

Main Results:

• Congenital microglial deficiency in animal models does not affect postnatal brain development but leads to age-dependent neuropathology resembling CRL.
• The impact of Csf1r mutations is influenced by genetic background, with C57BL/6J mice showing unique susceptibility to perinatal mortality and hydrocephalus.
• Current models do not fully replicate the severe motor and cognitive impairments observed in human patients.

Conclusions:

• Microglial deficiency contributes to age-dependent neuropathology and CRL.
• Existing animal models provide valuable platforms for investigating CRL pathogenesis and testing therapeutic strategies.
• Further research is needed to address species differences and environmental factors in CRL.