STIP1/HOP promotes the formation of cytotoxic α-synuclein oligomers

作者：Benjamin S. Rutledge, Carter J. Wilson, Rachel M. Lau, Juan C. Jurado‐Coronel, Esther del Cid‐Pellitero, Mikko Karttunen, Thomas M. Durcan, Edward A. Fon, Marco A. M. Prado, Justin Legleiter, Martin L. Duennwald, Wing‐Yiu Choy · 发表于：Molecular Neurodegeneration Advances · 年份：2026 · DOI：10.1186/s44477-026-00030-3 · 被引用次数：2 · 研究领域：Plant-based Medicinal Research、Toxin Mechanisms and Immunotoxins、PARP inhibition in cancer therapy

Background: The accumulation of alpha-synuclein (a-Syn) as toxic oligomers, and subsequently in Lewy bodies, is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Molecular chaperones and cochaperones are expected to act in concert to maintain physiological activities of proteins, including a-Syn, but in neurodegeneration this process can become mal-adaptive. Transcript levels of Stress inducible phosphoprotein 1 (STIP1), a co-chaperone of Hsp90/Hsp70, are elevated in brain samples from PD patients. In synucleinopathy mouse models, STIP1 has unexpected bidirectional effects on a-Syn, with overexpression of STIP1 aggravating a-Syn toxicity, whereas knockdown of STIP1 improves toxicity and behavioural phenotypes. However, it is unclear how STIP1 enhances the toxicity of a-Syn. Methods: Here we investigate the direct impact of the interaction between STIP1 and a-Syn on the aggregation kinetics of a-Syn using a diverse and integrated set of techniques, including Nuclear Magnetic Resonance (NMR), molecular dynamics simulation, aggregation kinetics assays, electron microscopy, atomic force microscopy, and dynamic light scattering. The toxicity of a-Syn aggregates formed in the presence of STIP1 was assessed using yeast models and SH-SY5Y cell assays. Results: We unravel the mechanisms by which STIP1/HOP regulates the neurotoxicity of a-Syn. Specifically, two binding motifs in the C-terminus of a-Syn directly interact with the TPR2A domain of STIP1/HOP ...