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Background <p>Aggregation of misfolded mutant Huntingtin (mHTT) is a pathological characteristic in Huntington’s disease (HD), implying clearance of mHTT is a therapeutical direction for this neurodegenerative disorder. Based on previous studies, Insulin-like growth factor 2 (IGF2) enhances microfilament polymerization in HD models; however, the role of IGF2 against mHTT aggregates is still unclear.</p> Results <p>Here, we demonstrate that IGF2 expression is significantly lower in symptomatic HD patients compared to presymptomatic individuals, and IGF2 activation mechanistically enhances phosphorylation of Protein Kinase B(AKT; serine/threonine kinase), which subsequently reduces mHTT aggregates in vitro. Furthermore, IGF2 stimulates Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, promoting the secretion of mHTT within extracellular vesicles, thereby aiding cellular clearance. In vivo studies in R6/2 HD transgenic mice reveal that IGF2 administration improves motor functions and decreases mHTT levels.</p> Conclusions <p>Collectively, our findings elucidate the multifaceted role of IGF2 in HD, highlighting its therapeutic potential through modulation of AKT and NF-κB signaling pathways.</p>

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Insulin-like growth factor 2 reduces Huntington’s disease aggregates via AKT and NF-κB signaling in huntington’s disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月26日

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  • Yun-Shiuan Tung,
  • Chih-Wei Tung,
  • Siew Chin Chan,
  • Yi-Ching Chen,
  • Po-Ming Wu,
  • Pei-Hsun Cheng,
  • Chuan-Mu Chen,
  • Shang-Hsun Yang

摘要

Background

Aggregation of misfolded mutant Huntingtin (mHTT) is a pathological characteristic in Huntington’s disease (HD), implying clearance of mHTT is a therapeutical direction for this neurodegenerative disorder. Based on previous studies, Insulin-like growth factor 2 (IGF2) enhances microfilament polymerization in HD models; however, the role of IGF2 against mHTT aggregates is still unclear.

Results

Here, we demonstrate that IGF2 expression is significantly lower in symptomatic HD patients compared to presymptomatic individuals, and IGF2 activation mechanistically enhances phosphorylation of Protein Kinase B(AKT; serine/threonine kinase), which subsequently reduces mHTT aggregates in vitro. Furthermore, IGF2 stimulates Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling, promoting the secretion of mHTT within extracellular vesicles, thereby aiding cellular clearance. In vivo studies in R6/2 HD transgenic mice reveal that IGF2 administration improves motor functions and decreases mHTT levels.

Conclusions

Collectively, our findings elucidate the multifaceted role of IGF2 in HD, highlighting its therapeutic potential through modulation of AKT and NF-κB signaling pathways.