Lipidic α-synuclein fibrils catalyze the formation of pathological mature fibrils

The aggregation of alpha-synuclein into amyloid fibrils is a defining characteristic of a group of neurodegenerative disorders called synucleinopathies, such as Parkinson's disease. The interaction between alpha-synuclein and lipid membranes influences the aggregation process, leading to the formation of protofibrils comprised of both protein and lipid, known as lipidic fibrils.

These lipidic fibrils can further mature into fibrils that resemble those extracted from Lewy bodies present in post-mortem brain samples of Parkinson's disease patients. In order to examine the impact of lipids and lipidic fibrils on the development of mature fibrils, the researchers employed a combination of experiments and kinetic theory.

The findings indicate that lipidic fibrils facilitate mature fibril formation through a heterogeneous primary nucleation mechanism, which reduces the activation energy barrier for mature fibril formation compared to lipid-independent primary nucleation. The subsequent stage of the reaction is determined by the rate at which protein monomers detach from the metastable lipidic fibrils, suggesting that fibrils form in order of stability according to Ostwald's Rule of Stages.

This mechanism was confirmed using the small molecule inhibitor ambroxol, which selectively inhibits lipidic fibril formation and shifts the aggregation kinetics to the slow, lipid-independent pathway. In summary, the results demonstrate that lipidic fibrils function as on-pathway intermediates, accelerating the aggregation of mature fibrils, potentially offering a quantitative approach to develop new therapeutic strategies aimed at inhibiting the pathological aggregation of alpha-synuclein.