Aguirre, C. | Search bioRxiv

bioRxiv2022

Conformational change in the monomeric alpha-synuclein imparts fibril polymorphs

-Synuclein (Syn) inclusions are a pathological hallmark of several neurodegenerative disorders. While cryo-electron microscopy studies have revealed distinct fibril polymorphs across different synucleinopathies, the molecular switches controlling polymorphism remained unveiled. In this study, we found that fibril morphology is associated with the conformational state of monomeric Syn. Through systematic manipulation of the ionic strength and temperature, we pinpoint two distinct polymorphs: a twisted morphology at low ionic strength and temperature, and a rod-like morphology at higher ionic strength and temperature. Most strikingly, we found that a specific conformational change in the C-terminal domain of the monomeric Syn serves as the master switch for the formation of polymorphs. Interestingly, this conformational change can be triggered by calcium binding to the C-terminus, connecting environmental factors to specific fibril architectures. Our results unmask the C-terminal domain as a key player for orchestrating Syn fibril morphology, providing significant insights into the fibrogenesis of Syn. Significance StatementThe Syn C-terminus domain acts as the master switch programming its fibril polymorphism.

biophysics↗

bioRxiv2022

Macromolecular crowding and supersaturation protect hemodialysis patients from the onset of dialysis-related amyloidosis

Dialysis-related amyloidosis (DRA), a serious complication among long-term hemodialysis patients, is caused by amyloid fibrils of {beta}2-microglobulin ({beta}2m). Although high serum {beta}2m levels and a long dialysis vintage are the primary and secondary risk factors for the onset of DRA, respectively, patients with these do not always develop DRA, indicating that there are additional risk factors. To clarify these unknown factors, we investigated the effects of human sera on {beta}2m amyloid fibril formation. Although sera markedly inhibited amyloid fibril formation, the inhibitory effects were weaker for sera collected from dialysis patients than for control sera. When sera collected before and after maintenance dialysis treatments were compared, the latter inhibited amyloid fibril formation more than the former. These results indicate that, although the inhibitory effects of sera were deteriorated in long-term dialysis patients, they were ameliorated by maintenance dialysis treatments in the short term. Maintenance dialysis decreases the body weight by 5% and consequently increases the concentrations of serum components. Among these components, we found that serum albumin prevented amyloid fibril formation based on macromolecular crowding effects, and that the decreased serum albumin concentration in dialysis patients is a tertiary risk factor for the onset of DRA. The model was constructed assuming accumulative effects of three risk factors and may be useful for predicting the onset of DRA. Furthermore, the model suggested the importance of monitoring temporary and accumulated risks to prevent the development of amyloidoses in general, which occurs based on supersaturation-limited amyloid fibril formation in a crowded milieu.

biophysics↗