Evidence map›Paper›PMID 42291828›Full record

ArticleMolecular neurodegeneration advances2026

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

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 and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular neurodegeneration advances, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.

0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

2 citing papers in PubMed.

  1. Article
  2. Improving Conformational Ensembles of Folded Proteins in Go̅Martini.Journal of chemical theory and computation · 2026
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

Benjamin S RutledgeDepartment of Biochemistry, The University of Western Ontario, London, ON Canada.
Carter J WilsonComputational Biomolecular Dynamics Group, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
Rachel M LauDepartment of Biochemistry, The University of Western Ontario, London, ON Canada.
Juan C Jurado-CoronelDepartment of Anatomy & Cell Biology, The University of Western Ontario, London, ON Canada.
Esther Del Cid-PelliteroEarly Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC Canada.
Mikko KarttunenDepartment of Chemistry, The University of Western Ontario, London, ON Canada.
Thomas M DurcanEarly Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC Canada.
Edward A FonEarly Drug Discovery Unit, Montreal Neurological Institute-Hospital, McGill University, Montreal, QC Canada.
Marco A M PradoDepartment of Anatomy & Cell Biology, The University of Western Ontario, London, ON Canada.
Justin LegleiterDepartment of Biochemistry & Molecular Biology, University of Nevada, Reno, USA.
Martin L DuennwaldDepartment of Anatomy & Cell Biology, The University of Western Ontario, London, ON Canada.
Wing-Yiu ChoyDepartment of Biochemistry, The University of Western Ontario, London, ON Canada.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

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. Supplementary Information: The online version contains supplementary material available at 10.1186/s44477-026-00030-3.

Indexed as

Alpha-synucleinChaperonesHsp-organizing proteinNeurotoxicityProtein aggregationProtein fibrilProtein homeostasisProtein misfoldingStress inducible phosphoprotein 1Synucleinopathy

Identifiers

PMID42291828
PMCPMC13253660

What OpenQuestion holds

Textmetadata
LicenceCC BY-NC-ND
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.