
@article {115046,
	title = {α-Synuclein aggregation intermediates form fibril polymorphs with distinct prion-like properties.},
	journal = {J Mol Biol},
	year = {2022},
	month = {2022 Jul 27},
	pages = {167761},
	abstract = {<p>α-Synuclein (α-Syn) amyloids in synucleinopathies are suggested to be structurally and functionally diverse, reminiscent of prion-like strains. But how the aggregation of the same precursor protein results in the formation of fibril polymorphs remains elusive. Here, we demonstrate the structure-function relationship of two polymorphs, pre-matured fibrils (PMFs) and helix-matured fibrils (HMFs), based on α-Syn aggregation intermediates. These polymorphs display the structural differences as demonstrated by solid-state NMR and mass spectrometry studies and also possess different cellular activities such as seeding, internalization, and cell-to-cell transfer of aggregates. HMFs with a compact core structure exhibit low seeding potency but readily internalize and transfer from one cell to another. The less structured PMFs lack transcellular transfer ability but induce abundant α-Syn pathology and trigger the formation of aggresomes in cells. Overall, the study highlights that the conformational heterogeneity in the aggregation pathway may lead to fibril polymorphs with distinct prion-like behavior.</p>
},
	issn = {1089-8638},
	doi = {10.1016/j.jmb.2022.167761},
	author = {Mehra, Surabhi and Ahlawat, Sahil and Kumar, Harish and Datta, Debalina and Navalkar, Ambuja and Singh, Nitu and Patel, Komal and Gadhe, Laxmikant and Kadu, Pradeep and Kumar, Rakesh and Jha, Narendra N and Sakunthala, Arunima and Sawner, Ajay S and Padinhateeri, Ranjith and Udgaonkar, Jayant B and Agarwal, Vipin and Maji, Samir K}
}
@article {78265,
	title = {α-Synuclein aggregation nucleates through liquid-liquid phase separation.},
	journal = {Nat Chem},
	year = {2020},
	month = {2020 Jun 08},
	abstract = {<p>α-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson{\textquoteright}s disease pathogenesis. However, the early events involved in this process remain unclear. Here, using the in vitro reconstitution and cellular model, we show that liquid-liquid phase separation of α-Syn precedes its aggregation. In particular, in vitro generated α-Syn liquid-like droplets eventually undergo a liquid-to-solid transition and form an amyloid hydrogel that contains oligomers and fibrillar species. Factors known to aggravate α-Syn aggregation, such as low pH, phosphomimetic substitution and familial Parkinson{\textquoteright}s disease mutations, also promote α-Syn liquid-liquid phase separation and its subsequent maturation. We further demonstrate α-Syn liquid-droplet formation in cells. These cellular α-Syn droplets eventually transform into perinuclear aggresomes, the process regulated by microtubules. This work provides detailed insights into the phase-separation behaviour of natively unstructured α-Syn and its conversion to a disease-associated aggregated state, which is highly relevant in Parkinson{\textquoteright}s disease pathogenesis.</p>
},
	issn = {1755-4349},
	doi = {10.1038/s41557-020-0465-9},
	author = {Ray, Soumik and Singh, Nitu and Kumar, Rakesh and Patel, Komal and Pandey, Satyaprakash and Datta, Debalina and Mahato, Jaladhar and Panigrahi, Rajlaxmi and Navalkar, Ambuja and Mehra, Surabhi and Gadhe, Laxmikant and Chatterjee, Debdeep and Sawner, Ajay Singh and Maiti, Siddhartha and Bhatia, Sandhya and Gerez, Juan Atilio and Chowdhury, Arindam and Kumar, Ashutosh and Padinhateeri, Ranjith and Riek, Roland and Krishnamoorthy, G and Maji, Samir K}
}
