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Direct Demonstration of Seed Size-Dependent α-Synuclein Amyloid Amplification
Journal
Journal of Physical Chemistry Letters
Date Issued
2022-07-21
Author(s)
Sakunthala, Arunima
Datta, Debalina
Navalkar, Ambuja
Gadhe, Laxmikant
Kadu, Pradeep
Patel, Komal
Mehra, Surabhi
Kumar, Rakesh
Chatterjee, Debdeep
Devi, Jyoti
Sengupta, Kundan
Padinhateeri, Ranjith
Maji, Samir K.
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.
Volume
13