Researchers have identified the molecular mechanism that causes the brain’s natural repair capacity to decline after stroke and have developed a potential therapy to extend the recovery window. The findings were published in Nature.
After a stroke, microglia, the brain’s resident immune cells, transition into a reparative state, producing growth factors such as insulin-like growth factor 1 (IGF1) that support remyelination, strengthen neural connections, and promote functional recovery. However, this reparative phase typically lasts only about two months before declining.
A team led by researchers from the Institute of Science, Tokyo, in collaboration with institutions in Japan and Germany, discovered that a transcription factor called ZFP384 increases as the brain’s repair functions diminish. ZFP384 disrupts the chromatin interactions mediated by the protein YY1 that are necessary for neural repair gene expression, causing microglia to lose their reparative properties.
When researchers genetically deleted the Zfp384 gene from microglia in mouse stroke models, the animals maintained recovery-associated gene expression for much longer than normal mice. This sustained reparative state enhanced remyelination of damaged nerve fibres and promoted synaptic plasticity, resulting in significantly better long-term neurological function.
Based on these findings, the team developed an antisense oligonucleotide (ASO) therapy designed to suppress Zfp384 expression. Remarkably, the treatment remained effective even when administered one week or one month after stroke onset.
Examination of brain tissue from human stroke patients revealed that ZNF384 (the human equivalent of ZFP384) increased as IGF1 declined, suggesting the mechanism operates in humans and could represent a therapeutic target.
The researchers plan to evaluate the safety and efficacy of ZFP384-targeting therapies in larger preclinical models before progressing to clinical trials.
Source: Medical Xpress / Institute of Science Tokyo (Nature, 2026)
