Structural polymorphism of α -synuclein fibrils alters pathway of Hsc70 mediated disaggregation

The 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 a unique toxic gain-of-function profile. 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 proteostasis network. Amyloid conformation influences not only how efficiently fibrils are cleared by the Hsc70 machinery but also the preferred pathway of disaggregation. We further show that, in vitro , the active processing of fibrils by the Hsc70 machinery inadvertently produces seeding competent species that further promote protein aggregation. Amyloid conformation thus is an important feature that can tilt the balance between beneficial or detrimental protein quality control activities in the context of disease.