biostudies-literatureJager SBundesministerium für Bildung und ForschungDeutsche Forschungsgemeinschaft (DFG)Agence Nationale de la Recherche (ANR)Association France ParkinsonAgence Nationale de la RechercheAlzheimer Forschung Initiative (AFI)Lundbeck Foundation (Lundbeckfonden)Association France Parkinson (France Parkinson)Alzheimer Forschung InitiativeBundesministerium für Bildung und Forschung (BMBF)Lundbeck FoundationDeutsche ForschungsgemeinschaftNovo Nordisk Fonden (NNF)Dutch Research Council (NWO)NWO | Exacte en Natuurwetenschappen (ENW)Novo Nordisk FondenNWO | Exacte en Natuurwetenschappen6499-6526https://www.ebi.ac.uk/biostudies/studies/S-EPMC12623964biostudies-literatureUnknown44(22)Pathological aggregation of α-synuclein into amyloid fibrils is a hallmark of synucleinopathies, including Parkinson's disease. Despite this commonality, synucleinopathies display divergent disease phenotypes that have been attributed to disease-specific three-dimensional structures of α-synuclein fibrils, each with unique toxic gain-of-function profiles. The Hsc70 chaperone is remarkable in its ability to disassemble pre-existing amyloid fibrils of different proteins in an ATP and co-chaperone-dependent manner. We find, however, using six well-defined conformational polymorphs of α-synuclein fibrils, that the activity of the Hsc70 disaggregase machinery is sensitive to differences in the amyloid conformation, confirming that fibril polymorphism directly affects interactions with the proteThe EMBO journalStructural polymorphism of α-synuclein fibrils alters the pathway of Hsc70-mediated disaggregation.PMC1262396401ED1807A17054VI.Vidi.223.17201ED1807B217681504257241NNFSA170028392ANR-22-PERM-0006ANR-17-JPCD-0005-01R366-2021-169Redeker VTittelmeier JWentink ASBellande TDang TLMelki RNussbaum-Krammer CBuell AKHennig JBukau BJager SfalseStructural polymorphism of α-synuclein fibrils alters the pathway of Hsc70-mediated disaggregation.Pathological aggregation of α-synuclein into amyloid fibrils is a hallmark of synucleinopathies, including Parkinson's disease. Despite this commonality, synucleinopathies display divergent disease phenotypes that have been attributed to disease-specific three-dimensional structures of α-synuclein fibrils, each with unique toxic gain-of-function profiles. The Hsc70 chaperone is remarkable in its ability to disassemble pre-existing amyloid fibrils of different proteins in an ATP and co-chaperone-dependent manner. We find, however, using six well-defined conformational polymorphs of α-synuclein fibrils, that the activity of the Hsc70 disaggregase machinery is sensitive to differences in the amyloid conformation, confirming that fibril polymorphism directly affects interactions with the prote2025-01-01T00:00:00Z2025 Nov2026-07-15T06:09:29.883Z2026-06-30T03:22:06.919ZS-EPMC126239644105326110.1038/s44318-025-00573-3