Size-dependent secondary nucleation and amplification of α-synuclein amyloid fibrils

Sakunthala, A.; Datta, D.; Navalkar, A.; Gadhe, L.; Kadu, P.; Patel, K.; Mehra, S.; Kumar, R.; Chatterjee, D.; Sengupta, K.; Padinhateeri, R.; Maji, S. K.

doi:10.1101/2021.12.28.474324

bioRxiv · 10.1101/2021.12.28.474324

Size-dependent secondary nucleation and amplification of α-synuclein amyloid fibrils

Sakunthala, A.·Datta, D.·Navalkar, A.·Gadhe, L.·Kadu, P.·Patel, K.·Mehra, S.·Kumar, R.·Chatterjee, D.·Sengupta, K.·Padinhateeri, R.·Maji, S. K.

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Abstract

The size of the 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 -synuclein (-Syn) fibrils are largely unknown. Using the cellular model and in vitro reconstitution, we showed that the size of -Syn fibril seeds not only dictates its cellular internalization and associated cell death; but also the distinct mechanisms of fibril amplification pathways involved in the pathological conformational change of -Syn. Specifically, small-sized 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 different sizes of seeds determine the underlying pathological outcome of synucleinopathies.

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Sakunthala, A., Datta, D., Navalkar, A., Gadhe, L., Kadu, P., Patel, K., Mehra, S., Kumar, R., Chatterjee, D., Sengupta, K., Padinhateeri, R., Maji, S. K.. 2021-12-28. Size-dependent secondary nucleation and amplification of α-synuclein amyloid fibrils. https://doi.org/10.1101/2021.12.28.474324

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