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<p>Parkinson’s disease (PD) is a common neurodegenerative movement disorder characterized by dopaminergic neuron loss in the substantia nigra pars compacta and striatal dopamine depletion. The <i>NUS1</i> gene, which encodes the neurite outgrowth inhibitor B receptor (NgBR), has been recently identified as a novel risk gene for PD. However, its roles and mechanism in neurodegeneration are still unclear. Here, we demonstrate that NgBR deficiency triggers neuronal damage through a novel KAT7/RFX1/FGF1 axis. RNA sequencing and experimental verification revealed that NgBR depletion downregulates expression and secretion of fibroblast growth factor 1 (FGF1), which led to inactivation of the PI3K/AKT signaling pathway. Mechanistically, NgBR deletion suppresses lysine acetyltransferase 7 (KAT7) expression, impairing KAT7-mediated acetylation of regulatory factor X1 (RFX1), a transcriptional repressor for <i>FGF1</i>. This stabilized RFX1 by blocking its proteasomal degradation, thereby suppressing <i>FGF1</i> transcription. Crucially, exogenous FGF1 rescued AKT signaling and mitigated neuronal damage in NgBR-deficient models. Our findings establish NgBR-KAT7-RFX1 as a regulatory axis controlling FGF1-dependent neuroprotection, which promotes the understanding of PD pathogenesis and highlights FGF1 supplementation as a potential therapeutic strategy.</p>

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Loss of NgBR causes neuronal damage through decreasing KAT7-mediated RFX1 acetylation and FGF1 expression

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月7日

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  • Yuwei Hu,
  • Yanni Ma,
  • Lele Liu,
  • Yan Hong,
  • Guanghui Wang,
  • Beisha Tang,
  • Jifeng Guo,
  • Peng Yang,
  • Ying Cao,
  • Haigang Ren

摘要

Parkinson’s disease (PD) is a common neurodegenerative movement disorder characterized by dopaminergic neuron loss in the substantia nigra pars compacta and striatal dopamine depletion. The NUS1 gene, which encodes the neurite outgrowth inhibitor B receptor (NgBR), has been recently identified as a novel risk gene for PD. However, its roles and mechanism in neurodegeneration are still unclear. Here, we demonstrate that NgBR deficiency triggers neuronal damage through a novel KAT7/RFX1/FGF1 axis. RNA sequencing and experimental verification revealed that NgBR depletion downregulates expression and secretion of fibroblast growth factor 1 (FGF1), which led to inactivation of the PI3K/AKT signaling pathway. Mechanistically, NgBR deletion suppresses lysine acetyltransferase 7 (KAT7) expression, impairing KAT7-mediated acetylation of regulatory factor X1 (RFX1), a transcriptional repressor for FGF1. This stabilized RFX1 by blocking its proteasomal degradation, thereby suppressing FGF1 transcription. Crucially, exogenous FGF1 rescued AKT signaling and mitigated neuronal damage in NgBR-deficient models. Our findings establish NgBR-KAT7-RFX1 as a regulatory axis controlling FGF1-dependent neuroprotection, which promotes the understanding of PD pathogenesis and highlights FGF1 supplementation as a potential therapeutic strategy.