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Fig. 8 | Molecular Brain

Fig. 8

From: mGluR5 regulates REST/NRSF signaling through N-cadherin/β-catenin complex in Huntington’s disease

Fig. 8

Schematic representation of the proposed model for the modulation of REST/NRSF signaling by mGluR5 and mHTT. a Shown is a schematic for mGluR5 signaling modulation by both mGluR5 agonist, DHPG, and the mGluR5-selective negative allosteric modulator, CTEP in the presence of HTT. mGluR5 induces Src family phosphorylation that phosphorylates N-cadherin at Y860, and this phosphorylation site in N-cadherin disrupts its interaction with β-catenin in cellular membrane. Then, β-catenin is released to cytoplasm and translocates to the nucleus, which becomes available to bind the TCF/LEF family of transcription factors to induce target gene expression, such as REST/NRSF. Under basal conditions, HTT sequesters REST/NRSF in the cytoplasm, thereby preventing it from forming the nuclear co-repressor complex at the RE1/NRSE nuclear site, allowing the transcription of REST/NRSF target gene, such as SNAP-25. SNAP-25 could affect the brain-derived neurotrophic factor (BDNF) release, supporting the survival of the striatal medium-sized spiny neurons. b The presence of mHTT enhances mGluR5-dependent Src activation, which culminates an increase of N-cadherin phosphorylation. Also, mHTT cannot retain REST/NRSF in the cytosol, causing the pathological entry of REST/NRSF into the nucleus, reducing SNAP-25 gene transcription and potentially BDNF release, which is correlated to neuronal death

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