ArticleThe Journal of biological chemistry
Hsp70 chaperone blocks α-synuclein oligomer formation via a novel engagement mechanism.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed.
- Convergent Astrocytic Failure in Parkinson's Disease: A System-Level Model of Pathogenesis and Treatment.Molecular neurobiology · 2026Review
- Endogenous Expression of HSP70 and Thioredoxin-1 During Methamphetamine-Induced Degeneration.Biomedicines · 2026Article
- Heat shock proteins (Hsp70 and Hsp90) in neurodegeneration: pathogenic roles and therapeutic potential.Frontiers in aging neuroscience · 2026Review
- STIP1/HOP promotes the formation of cytotoxic α-synuclein oligomers.Molecular neurodegeneration advances · 2026Article
- Intracellular aggregation of the transthyretin protein is limited by Hsp70 chaperones.bioRxiv : the preprint server for biology · 2025Article
- Controlling interfacial protein adsorption, desorption and aggregation in biomolecular condensates.Nature communications · 2025Article
- Review
- The Search for Disease Modification in Parkinson's Disease-A Review of the Literature.Life (Basel, Switzerland) · 2025Review
- Thermal Cycling-Hyperthermia Attenuates Rotenone-Induced Cell Injury in SH-SY5Y Cells Through Heat-Activated Mechanisms.International journal of molecular sciences · 2025Article
- Hsp70: A Multifunctional Chaperone in Maintaining Proteostasis and Its Implications in Human Disease.Cells · 2025Review
- Article
- DnaK duplication and specialization in bacteria correlates with increased proteome complexity.mSystems · 2024Article
- Linking Heat Shock Protein 70 and Parkin in Parkinson's Disease.Molecular neurobiology · 2023Review
- Inhibition of Protein Aggregation and Endoplasmic Reticulum Stress as a Targeted Therapy for α-Synucleinopathy.Pharmaceutics · 2023Review
- Neurodegenerative Proteinopathies Induced by Environmental Pollutants: Heat Shock Proteins and Proteasome as Promising Therapeutic Tools.Pharmaceutics · 2023Review
- ZNF330/NOA36 interacts with HSPA1 and HSPA8 and modulates cell cycle and proliferation in response to heat shock in HEK293 cells.Biology direct · 2023Article
- Oligomeric State and Holding Activity of Hsp60.International journal of molecular sciences · 2023Article
- Taking Charge: Metal Ions Accelerate Amyloid Aggregation in Sequence Variants of α-Synuclein.Journal of the American Society for Mass Spectrometry · 2023Article
- Genetic modifiers of synucleinopathies-lessons from experimental models.Oxford open neuroscience · 2023Review
- Comprehensive characterization of the Hsp70 interactome reveals novel client proteins and interactions mediated by posttranslational modifications.PLoS biology · 2022Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
Overexpression and aggregation of α-synuclein (ASyn) are linked to the onset and pathology of Parkinson's disease and related synucleinopathies. Elevated levels of the stress-induced chaperone Hsp70 protect against ASyn misfolding and ASyn-driven neurodegeneration in cell and animal models, yet there is minimal mechanistic understanding of this important protective pathway. It is generally assumed that Hsp70 binds to ASyn using its canonical and promiscuous substrate-binding cleft to limit aggregation. Here we report that this activity is due to a novel and unexpected mode of Hsp70 action, involving neither ATP nor the typical substrate-binding cleft. We use novel ASyn oligomerization assays to show that Hsp70 directly blocks ASyn oligomerization, an early event in ASyn misfolding. Using truncations, mutations, and inhibitors, we confirm that Hsp70 interacts with ASyn via an as yet unidentified, noncanonical interaction site in the C-terminal domain. Finally, we report a biological role for a similar mode of action in H4 neuroglioma cells. Together, these findings suggest that new chemical approaches will be required to target the Hsp70-ASyn interaction in synucleinopathies. Such approaches are likely to be more specific than targeting Hsp70's canonical action. Additionally, these results raise the question of whether other misfolded proteins might also engage Hsp70 via the same noncanonical mechanism.
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Registered trials
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.