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

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