Scholarlink

<p>Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein aggregation and lysosomal dysfunction, with <i>GBA1</i> mutations representing the most common genetic risk factor. Reduced glucocerebrosidase (GCase) activity is observed in both familial and sporadic PD, promoting α-synuclein accumulation and neuronal toxicity. Here, we developed a GBA1-HiBiT tagged knock-in HEK293T reporter system, providing a highly sensitive, real-time quantitative measurement of GCase dynamics. From a leech-derived peptide library, we identified a cell-penetrating peptide hirunipin 4 that significantly enhanced GCase protein levels and enzymatic activity. Moreover, hirunipin 4 alleviated α-synuclein preformed fibrils (PFF)-induced lysosomal dysfunction and glucosylceramide accumulation. Thus, hirunipin 4 was able to reduce PFF-induced pathological α-synuclein accumulation and neurotoxicity in both SH-SY5Y and primary cortical neurons. Mechanistically, hirunipin 4 promoted nuclear translocation of TFEB and enhanced GCase protein stability. These findings highlight the utility of the GBA1-HiBiT platform for peptide-based screening and identify hirunipin 4 as a promising candidate for restoring lysosomal function in PD.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

A novel peptide-based strategy to enhance GBA1 expression for treating Parkinson’s disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年11月19日

查看全文
  • Hyerynn Kim,
  • Jiyeon Na,
  • Hye Guk Ryu,
  • Eunmin Lee,
  • Hyeonwoo Park,
  • Haeun Park,
  • Younwoo Nam,
  • Geon-Hwi Jeong,
  • In-Hyeok Pyo,
  • Jung-Hyun Choi,
  • Jihoon Nah,
  • Sang-Min Jang,
  • Jun-Ho Song,
  • Sung-Jin Cho,
  • Sangjune Kim

摘要

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein aggregation and lysosomal dysfunction, with GBA1 mutations representing the most common genetic risk factor. Reduced glucocerebrosidase (GCase) activity is observed in both familial and sporadic PD, promoting α-synuclein accumulation and neuronal toxicity. Here, we developed a GBA1-HiBiT tagged knock-in HEK293T reporter system, providing a highly sensitive, real-time quantitative measurement of GCase dynamics. From a leech-derived peptide library, we identified a cell-penetrating peptide hirunipin 4 that significantly enhanced GCase protein levels and enzymatic activity. Moreover, hirunipin 4 alleviated α-synuclein preformed fibrils (PFF)-induced lysosomal dysfunction and glucosylceramide accumulation. Thus, hirunipin 4 was able to reduce PFF-induced pathological α-synuclein accumulation and neurotoxicity in both SH-SY5Y and primary cortical neurons. Mechanistically, hirunipin 4 promoted nuclear translocation of TFEB and enhanced GCase protein stability. These findings highlight the utility of the GBA1-HiBiT platform for peptide-based screening and identify hirunipin 4 as a promising candidate for restoring lysosomal function in PD.