biostudies-literatureDing NNational Natural Science Foundation of ChinaLin gang LaboratoryShanghaiTech University1298-1315https://www.ebi.ac.uk/biostudies/studies/S-EPMC12087658biostudies-literatureUnknown21(6)The CGG repeat expansions in the 5'-UTR regions of certain genes have been implicated in various neurodegenerative and muscular disorders. However, the underlying pathogenic mechanisms are not well understood. In this study, we explore the role of the small molecular chaperone HSPB1 in counteracting neurodegeneration induced by poly-glycine (poly-G) aggregates. Employing a reporter system, we demonstrate that CGG repeat expansions within the 5'-UTR of the <i>GIPC1</i> gene produce poly-G proteins, by repeat-associated non-AUG (RAN) translation. Through proximity labeling and subsequent mass spectrometry analysis, we characterize the composition of poly-G insoluble aggregates and reveal that these aggregates sequester key macroautophagy/autophagy receptors, SQSTM1/p62 and TOLLIP. This sequeAutophagyHeat-shock chaperone HSPB1 mitigates poly-glycine-induced neurodegeneration via restoration of autophagic flux.PMC12087658LG-GG-202401-ADA06020031871044SLST-YS202400291949117Li WLi XZhang YDing NYu WLi LSong YfalseHeat-shock chaperone HSPB1 mitigates poly-glycine-induced neurodegeneration via restoration of autophagic flux.The CGG repeat expansions in the 5'-UTR regions of certain genes have been implicated in various neurodegenerative and muscular disorders. However, the underlying pathogenic mechanisms are not well understood. In this study, we explore the role of the small molecular chaperone HSPB1 in counteracting neurodegeneration induced by poly-glycine (poly-G) aggregates. Employing a reporter system, we demonstrate that CGG repeat expansions within the 5'-UTR of the <i>GIPC1</i> gene produce poly-G proteins, by repeat-associated non-AUG (RAN) translation. Through proximity labeling and subsequent mass spectrometry analysis, we characterize the composition of poly-G insoluble aggregates and reveal that these aggregates sequester key macroautophagy/autophagy receptors, SQSTM1/p62 and TOLLIP. This seque2025-01-01T00:00:00Z2025 Jun2026-07-09T12:24:39.596Z2026-07-09T11:17:48.083ZS-EPMC120876583993662010.1080/15548627.2025.2466144