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α-Synuclein aggregation nucleates through liquid-liquid phase separation

Nature chemistry, 2020-08, Vol.12 (8), p.705-716 [Peer Reviewed Journal]

The Author(s), under exclusive licence to Springer Nature Limited 2020. ;ISSN: 1755-4330 ;EISSN: 1755-4349 ;DOI: 10.1038/s41557-020-0465-9 ;PMID: 32514159

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Title:
α-Synuclein aggregation nucleates through liquid-liquid phase separation
Author: Ray, Soumik ; Singh, Nitu ; Kumar, Rakesh ; Patel, Komal ; Pandey, Satyaprakash ; Datta, Debalina ; Mahato, Jaladhar ; Panigrahi, Rajlaxmi ; Navalkar, Ambuja ; Mehra, Surabhi ; Gadhe, Laxmikant ; Chatterjee, Debdeep ; Sawner, Ajay Singh ; Maiti, Siddhartha ; Bhatia, Sandhya ; Gerez, Juan Atilio ; Chowdhury, Arindam ; Kumar, Ashutosh ; Padinhateeri, Ranjith ; Riek, Roland ; Krishnamoorthy, G ; Maji, Samir K
Subjects: Agglomeration ; Aggresomes ; alpha-Synuclein - chemistry ; alpha-Synuclein - genetics ; alpha-Synuclein - metabolism ; Amyloid ; Droplets ; HeLa Cells ; Humans ; Hydrogels ; Hydrogen-Ion Concentration ; Liquid phases ; Microscopy, Confocal ; Microtubules ; Movement disorders ; Mutagenesis, Site-Directed ; Mutation ; Neurodegenerative diseases ; Nucleation ; Oligomers ; Parkinson Disease - metabolism ; Parkinson Disease - pathology ; Parkinson's disease ; Pathogenesis ; Phase separation ; Phase Transition ; Polyethylene Glycols - chemistry ; Protein Aggregates - physiology ; Recombinant Proteins - biosynthesis ; Recombinant Proteins - chemistry ; Recombinant Proteins - isolation & purification ; Synuclein
Is Part Of: Nature chemistry, 2020-08, Vol.12 (8), p.705-716
Description: α-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson'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'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's disease pathogenesis.
Publisher: England: Nature Publishing Group
Language: English
Identifier: ISSN: 1755-4330
EISSN: 1755-4349
DOI: 10.1038/s41557-020-0465-9
PMID: 32514159
Source: MEDLINE
ProQuest Central

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α-Synuclein aggregation nucleates through liquid-liquid phase separation

The Author(s), under exclusive licence to Springer Nature Limited 2020. ;ISSN: 1755-4330 ;EISSN: 1755-4349 ;DOI: 10.1038/s41557-020-0465-9 ;PMID: 32514159

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