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ASTROCYTIC MODULATION OF WNT5B-NFATC2 PATHWAY-DEPENDENT MMP14 EXPRESSION AMELIORATES NEUROPATHOLOGY IN HUNTINGTON'S DISEASE
Phuong Nguyenand 8 co-authors
Center for Brain Disorders, Brain Science Institute, Korea Institute of Science and Technology (KIST)
FENS Forum 2026 (2026)
Barcelona, Spain
Board PS05-09AM-282
Presentation
Date TBA
Board: PS05-09AM-282
Event Information
Poster Board
PS05-09AM-282
Poster
View posterAbstract
Huntington’s disease (HD) is a fatal neurodegenerative disorder characterized by involuntary movements, emotional disturbances, and cognitive impairment. Although dysregulated WNT signaling has been implicated in HD, its pathogenic role remains unclear. Herein, we show that astrocytic WNT5B mRNA and protein levels were elevated in the striatum of HD patients and HD model mice. Noncanonical WNT5B signaling sustained expression of the extracellular matrix (ECM)–degrading enzyme matrix metallopeptidase 14 (MMP14) through activation of the NFATc2 transcription factor in human and primary mouse astrocytes. MMP14 upregulation promoted ECM degradation, medium spiny neuron (MSN) damage, and increased mutant huntingtin aggregation in N171-82Q HD transgenic mice. WNT5B gain-of-function further exacerbated neuropathology, impaired motor coordination, and shortened lifespan of N171-82Q mice. Furthermore, we found that estrogen receptor α (ERα) overexpression suppresses NFATc2 transcriptional activity in vitro. Targeting the WNT5B–NFATc2–MMP14 axis with the phytoestrogen genistein reduced MMP14 transcription by antagonizing NFATc2, prevented ECM degradation, alleviated neuropathology and motor deficits, and extended survival in N171-82Q mice. Together, these findings identify astrocytic MMP14 induction via noncanonical WNT5B signaling as a driver of ECM degradation and MSN damage in HD, and suggest genistein-mediated modulation of this noncell-autonomous pathway as a potential therapeutic strategy.
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