2. Academic Validation
  3. Loss of NgBR causes neuronal damage through decreasing KAT7-mediated RFX1 acetylation and FGF1 expression

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

  • Cell Mol Life Sci. 2025 Apr 7;82(1):140. doi: 10.1007/s00018-025-05660-6.
Yuwei Hu 1,  Yanni Ma 1,  Lele Liu 1,  Yan Hong 1,  Guanghui Wang 1 2 3,  Beisha Tang 4,  Jifeng Guo 4,  Peng Yang 5,  Ying Cao 6,  Haigang Ren 7 8 9 10
Affiliations

Affiliations

  • 1 Department of Pharmacy, The Affiliated Zhangjiagang Hospital of Soochow University, Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
  • 2 Suzhou Key Laboratory of Geriatric Neurological Disorders, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215400, China.
  • 3 MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, Jiangsu, 215123, China.
  • 4 Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 5 Jiangsu Provincial Medical Innovation Center of Trauma Medicine, Institute of Trauma Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, China. yangpeng@suda.edu.cn.
  • 6 Department of Pharmacy, The Affiliated Zhangjiagang Hospital of Soochow University, Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China. caoyaoshi@126.com.
  • 7 Department of Pharmacy, The Affiliated Zhangjiagang Hospital of Soochow University, Laboratory of Molecular Neuropathology, Department of Pharmacology, Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China. rhg@suda.edu.cn.
  • 8 Suzhou Key Laboratory of Geriatric Neurological Disorders, The First People's Hospital of Taicang, Taicang Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215400, China. rhg@suda.edu.cn.
  • 9 MOE Key Laboratory of Geriatric Diseases and Immunology, Soochow University, Suzhou, Jiangsu, 215123, China. rhg@suda.edu.cn.
  • 10 Jiangsu Provincial Medical Innovation Center of Trauma Medicine, Institute of Trauma Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215123, China. rhg@suda.edu.cn.
PMID: 40192836 DOI: 10.1007/s00018-025-05660-6
Abstract

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.

Keywords

Acetylation; FGF1; NUS1/NgBR; Neuronal damage; Parkinson’s disease; RFX1.

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