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Background <p>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. </p> Methods <p>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&#xa0;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.</p> Results <p>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 in a dynamic manner, competing for a shared interface on TPR2A. Binding of STIP1/HOP to a-Syn attenuates the formation of a-Syn fibrils while promoting the accumulation of high molecular weight amorphous a-Syn species. Samples of a-Syn aggregated in the presence of STIP1/HOP contain significantly more A11-positive oligomeric species and cause a greater reduction in cell viability than a-Syn aggregated in the absence of STIP1/HOP in neuronal cells.</p> Conclusions <p>Our results provide a mechanism by which the direct interaction between STIP1/HOP and the C-terminus of a-Syn promotes the formation of cytotoxic, non-amyloidogenic, high molecular weight a-Syn species. Our model offers an explanation for the unexpected pathological link between STIP1 and a-Syn toxicity, thus opening new therapeutic avenues for the treatment of synucleinopathies.</p> <p><b>Classification: </b>Biological Sciences - Biochemistry</p>

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

  • 期刊论文

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  • 发表日期：

    2026年4月24日

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  • 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

摘要

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 in a dynamic manner, competing for a shared interface on TPR2A. Binding of STIP1/HOP to a-Syn attenuates the formation of a-Syn fibrils while promoting the accumulation of high molecular weight amorphous a-Syn species. Samples of a-Syn aggregated in the presence of STIP1/HOP contain significantly more A11-positive oligomeric species and cause a greater reduction in cell viability than a-Syn aggregated in the absence of STIP1/HOP in neuronal cells.

Conclusions

Our results provide a mechanism by which the direct interaction between STIP1/HOP and the C-terminus of a-Syn promotes the formation of cytotoxic, non-amyloidogenic, high molecular weight a-Syn species. Our model offers an explanation for the unexpected pathological link between STIP1 and a-Syn toxicity, thus opening new therapeutic avenues for the treatment of synucleinopathies.

Classification: Biological Sciences - Biochemistry