Direct Demonstration of Seed Size-Dependent α-Synuclein Amyloid Amplification
Arunima Sakunthala, Debalina Datta, Ambuja Navalkar, Laxmikant Gadhe, Pradeep Kadu, Komal Patel, Surabhi Mehra, Rakesh Kumar, Debdeep Chatterjee, Jyoti Devi, Kundan Sengupta, Ranjith Padinhateeri, Samir K. Maji
Abstract
The size of amyloid seeds is known to modulate their autocatalytic amplification and cellular toxicity. However, the seed size-dependent secondary nucleation mechanism, toxicity, and disease-associated biological processes mediated by α-synuclein (α-Syn) fibrils are largely unknown. Using the cellular model and in vitro reconstitution, we showed that the size of α-Syn fibril seeds dictates not only their cellular internalization and associated cell death but also the distinct mechanisms of fibril amplification pathways involved in the pathological conformational change of α-Syn. Specifically, small fibril seeds showed elongation possibly through monomer addition at the fibril termini, whereas longer fibrils template the fibril amplification by surface-mediated nucleation as demonstrated by super-resolution microscopy. The distinct mechanism of fibril amplification and cellular uptake along with toxicity suggest that breakage of fibrils into seeds of different sizes determines the underlying pathological outcome of synucleinopathies.