Astrocytic noncanonical WNT5B signaling modulates extracellular matrix remodeling and neuropathology in Huntington’s disease

Huntington's disease (HD) is a fatal neurodegenerative disorder characterized by a triad of behavioral symptoms: involuntary movement, emotional change, and cognitive dysfunction. Although alterations in WNT signaling have been reported in HD, its precise role in pathogenesis remains unclear. In this study, we found that astrocytic WNT5B mRNA and protein levels are elevated in the striatum of both HD patients and HD model mice. The noncanonical WNT5B signaling pathway induced sustained expression of matrix metallopeptidase 14 (MMP14), an extracellular matrix (ECM)-degrading enzyme, via activation of the NFATc2 transcription factor in both human and primary mouse astrocytes. Robust 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 demonstrated that the overexpression of the estrogen receptor α (ERα) suppresses NFATc2 transcriptional activity in vitro. A targeted therapy for the WNT5B-NFATc2-MMP14 signaling pathway by genistein, a phytoestrogen, reduced MMP14 transcription by antagonizing NFATc2 activity and preventing ECM degradation in N171-82Q mice. Genistein treatment also ameliorated neuropathology and motor deficits and prolonged the lifespan of HD mice. Together, these findings define a molecular pathological mechanism in which astrocytic MMP14 transcription, driven by the noncanonical WNT5B signaling pathway, promotes ECM degradation and MSN damage and accelerates neurodegeneration in HD. Modulation of the noncell-autonomous WNT5B-NFATc2-MMP14 signaling pathway by genistein may serve as a potential therapeutic strategy for mitigating HD pathogenesis.