Rudiger, S. | Search bioRxiv

bioRxiv2024

Fibril fragmentation generates diversity in seed population

Neurodegenerative diseases are characterised by the formation and accumulation of protein fibrils. The mechanism underlaying this aggregation process remains poorly understood. Fibril fragmentation, resulting in seed generation, plays a role in toxicity. Here we provide a quantitative picture of the impact of ultrasound on patient-derived and recombinant fibrils from various diseases. Fragmentation of recombinant Tau fibrils and patient-derived fibrils from Alzheimers Disease, Corticobasal Degeneration and Frontotemporal Dementia generates amyloid and non-amyloid species. Interestingly, patient-derived fibrils are more susceptible to ultrasound than artificial fibrils. Understanding fibril fragmentation and the generation and nature of seeds may provide insights to the molecular mechanism of the disease progression, contributing to the development therapeutic approaches.

biochemistry↗

bioRxiv2022

A peptide strategy for inhibiting different protein aggregation pathways in disease

Protein aggregation correlates with many human diseases. Protein aggregates differ in shape, ranging from amorphous aggregates to amyloid fibrils. Possibly for such heterogeneity, strategies to develop effective aggregation inhibitors that reach the clinic failed so far. Here, we present a new strategy by which we developed a family of peptides targeting early aggregation stages for both amorphous and fibrillar aggregates of proteins unrelated in sequence and structure. Thus, they act on dynamic precursors before a mechanistic differentiation takes place. Using a peptide array approach, we first identified peptides inhibiting the predominantly amorphous aggregation of a molten globular, aggregation-prone protein, a thermolabile mutant of the Axin tumor suppressor. A series of optimization steps revealed that the peptides activity did not depend on their sequences but rather on their molecular determinants. The key properties that made a peptide active were a composition of 20-30% flexible, 30-40% aliphatic and 20-30% aromatic residues, a hydrophobicity/hydrophilicity ratio close to 1 and an even distribution of residues of different nature throughout the sequence. Remarkably, the optimized peptides also suppressed fibrillation of Tau, a disordered protein that forms amyloids in Alzheimers disease, and entirely unrelated to Axin. Our compounds thus target early aggregation stages, independent of the aggregation mechanism, inhibiting both amorphous and amyloid aggregation. Such cross-mechanistic, multi-targeting aggregation inhibitors may be attractive lead compounds against multiple protein aggregation diseases.

biochemistry↗