{"database":"GEO","file_versions":[],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE294445"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Modulation of non-canonical WNT5B-NFATc2 pathway-dependent MMP14 expression in astrocytes ameliorates neuropathology and motor behaviors in Huntington's disease mice","description":"Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by a triad of behavioral symptoms, including involuntary movement, emotional change, and cognitive dysfunction. Although alterations in the WNT signaling pathway have been reported in HD, its precise role in disease pathogenesis remains unclear. In this study, we found that astrocytic WNT5B mRNA and protein levels were elevated in the striatum of both HD patients and HD mouse models. WNT5B induced prolonged expression of matrix metallopeptidase 14 (MMP14), an extracellular matrix (ECM)-degrading enzyme, through NFATc2 transcription factor activation via the non-canonical WNT signaling pathway in both human and primary mouse astrocytes. The significant upregulation of MMP14 led to ECM degradation, medium spiny neuron (MSN) damage, and increased mutant huntingtin aggregation in N171-82Q HD transgenic mice. Furthermore, WNT5B gain-of-function exacerbated neuropathology, impaired motor coordination, and shortened the lifespan of N171-82Q mice. We further report that overexpression of estrogen receptor (ER ) suppresses NFATc2 transcriptional activity. Genistein, a phytoestrogen, reduced MMP14 transcription by antagonizing the NFATc2 pathway and prevented ECM degradation in N171-82Q mice. Additionally, genistein administration ameliorated motor behavior and prolonged the lifespan of N171-82Q mice. Together, our findings reveal a molecular pathological mechanism in which astrocytic MMP14 transcription, activated by the non-canonical WNT5B signaling pathway, causes ECM degradation, MSN damage, and accelerates neurodegeneration in HD. Modulation of non-cell-autonomous WNT5B-NFATc2-MMP14 pathway by genistein may serve as a potential therapeutic strategy for ameliorating HD pathogenesis.","dates":{"publication":"2026/05/31"},"accession":"GSE294445","cross_references":{"GSM":["GSM8905559","GSM8905548","GSM8905558","GSM8905557","GSM8905555","GSM8905554","GSM8905553","GSM8905551","GSM8905550"],"GPL":["13112"],"GSE":["294445"],"taxon":["Mus musculus"]}}