CSF1R T567M mutation induces microglial dysfunction and synaptic impairment in patient iPSC-derived cerebral organoids of CSF1R-related disorder - PubMed
3 hours ago
- #CSF1R-related disorder
- #iPSC model
- #neurodegenerative disease
- CSF1R-related disorder (CSF1R-RD) is a rare neurodegenerative disease caused by mutations in the CSF1R gene.
- The study focuses on the novel CSF1R T567M mutation, located outside the tyrosine kinase domain, to understand its pathogenic impact.
- An iPSC model system was developed, including mutant (CSF1R-MT) and CRISPR/Cas9-corrected isogenic control lines.
- iPSC-derived microglia (iMGL) and cerebral organoids (COs) were generated to study the mutation's effects.
- RNA sequencing revealed altered genes and pathways involved in neuroinflammation in MT iMGL.
- CSF1R-MT caused haploinsufficiency, reduced autophosphorylation of CSF1R at Tyr546, and activated autophagy.
- MT iMGL showed increased phagocytosis, impaired migration, and induced neuroinflammation.
- Transcriptomic analysis indicated upregulation of immune activity and downregulation of synaptic function.
- CSF1R-MT promoted proliferation but inhibited neural differentiation and maturation in COs.
- Whole-cell patch-clamp recordings demonstrated impaired synaptic function in CSF1R-MT COs.
- The study highlights the critical role of CSF1R signaling in neural homeostasis and provides a platform for future therapeutic screening.