- Microglial PBRM1 deficiency causes altered microglial clustering, excessive neurogenesis and autism-like behaviours in mice.
- PBRM1 directly binds the Ccl5 promoter and represses CCL5 expression.
- Elevated CCL5 activates CCR1/5-β-catenin signalling to promote NSPC proliferation and neuronal differentiation; CCR1/5 blockade ameliorates behavioural deficits.
Adv Sci (Weinh). 2026 Oct 18:e78086. doi: 10.1002/advs.78086. Online ahead of print.
ABSTRACT
The prevalence of autism spectrum disorder (ASD), a heterogeneous neurodevelopmental disorder with limited effective therapeutic drugs, has been rising worldwide. Missense mutations in Polybromo 1 (Pbrm1), a core component of the SWI/SNF (switch/sucrose non-fermentable) chromatin remodeling complex, have been identified as a risk factor for ASD; however, whether PBRM1 loss of function contributes to the pathogenesis remains elusive. Here we provide direct evidence that microglial PBRM1 deficiency leads to altered microglial clusters, excessive neurogenesis, and ASD-like behaviors in mice. Integrated molecular analyses reveal that PBRM1 directly binds to the Ccl5 promoter and represses the expression of CCL5. Elevated CCL5 promotes the proliferation and neuronal differentiation of neural stem/progenitor cells (NSPCs) via the CCR1/5-β-catenin signaling pathway. Importantly, pharmacological blockade of CCR1/5 ameliorates behavioral deficits in Pbrm1 cKO mice. Together, these findings identify a previously unrecognized microglia-NSPC communication mechanism linking PBRM1 dysfunction to aberrant neurodevelopment and suggest the CCL5-CCR1/5 axis as a potential therapeutic target for ASD.
PMID:42893407 | DOI:10.1002/advs.78086
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