α-Synuclein aggregation intermediates form fibril polymorphs with distinct prion-like properties

Mehra, S.; Ahlawat, S.; Kumar, H.; Singh, N.; Navalkar, A.; Patel, K.; Kadu, P.; Kumar, R.; Jha, N. N.; Udgaonkar, J. B.; Agarwal, V.; Maji, S. K.

doi:10.1101/2020.05.03.074765

bioRxiv · 10.1101/2020.05.03.074765

α-Synuclein aggregation intermediates form fibril polymorphs with distinct prion-like properties

Mehra, S.·Ahlawat, S.·Kumar, H.·Singh, N.·Navalkar, A.·Patel, K.·Kadu, P.·Kumar, R.·Jha, N. N.·Udgaonkar, J. B.·Agarwal, V.·Maji, S. K.

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Abstract

-Synuclein (-Syn) amyloid fibrils in synucleinopathies (such as Parkinsons disease (PD), multiple system atrophy (MSA)) are structurally and functionally different, reminiscent of prion-like strains. However, how a single protein can form different fibril polymorphs in various synucleinopathies is not known. Here, we demonstrate the structure-function relationship of two distinct -Syn fibril polymorphs, the pre-matured fibrils (PMF) and helix-matured fibrils (HMF) based on -Syn aggregation intermediates. These polymorphs not only display the structural differences, including their fibril core structure as demonstrated by solid-state nuclear magnetic resonance (NMR) spectroscopy and H/D-exchange coupled with mass spectrometry but also possess different cellular activities such as seeding, cellular internalization, and cell-to-cell transmission. The HMF with a compact core structure exhibits low seeding potency in cells but readily internalizes and transmits from one cell to another. Whereas the less structured PMF lacks the cell-to-cell transmission ability but induces abundant -Syn pathology and triggers the formation of aggresomes in cells. Overall, the study highlights how the conformational heterogeneity in the aggregation pathway may lead to fibril polymorphs with distinct prion-like behavior in PD.

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Mehra, S., Ahlawat, S., Kumar, H., Singh, N., Navalkar, A., Patel, K., Kadu, P., Kumar, R., Jha, N. N., Udgaonkar, J. B., Agarwal, V., Maji, S. K.. 2020-05-04. α-Synuclein aggregation intermediates form fibril polymorphs with distinct prion-like properties. https://doi.org/10.1101/2020.05.03.074765

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