| First Author | Ralvenius WT | Year | 2023 |
| Journal | J Exp Med | Volume | 220 |
| Issue | 11 | PubMed ID | 37642942 |
| Mgi Jnum | J:347913 | Mgi Id | MGI:7609963 |
| Doi | 10.1084/jem.20222105 | Citation | Ralvenius WT, et al. (2023) A novel molecular class that recruits HDAC/MECP2 complexes to PU.1 motifs reduces neuroinflammation. J Exp Med 220(11) |
| abstractText | Pervasive neuroinflammation occurs in many neurodegenerative diseases, including Alzheimer's disease (AD). SPI1/PU.1 is a transcription factor located at a genome-wide significant AD-risk locus and its reduced expression is associated with delayed onset of AD. We analyzed single-cell transcriptomic datasets from microglia of human AD patients and found an enrichment of PU.1-binding motifs in the differentially expressed genes. In hippocampal tissues from transgenic mice with neurodegeneration, we found vastly increased genomic PU.1 binding. We then screened for PU.1 inhibitors using a PU.1 reporter cell line and discovered A11, a molecule with anti-inflammatory efficacy and nanomolar potency. A11 regulated genes putatively by recruiting a repressive complex containing MECP2, HDAC1, SIN3A, and DNMT3A to PU.1 motifs, thus representing a novel mechanism and class of molecules. In mouse models of AD, A11 ameliorated neuroinflammation, loss of neuronal integrity, AD pathology, and improved cognitive performance. This study uncovers a novel class of anti-inflammatory molecules with therapeutic potential for neurodegenerative disorders. |
