α‐Synuclein aggregation nucleates through liquid‐liquid phase separation
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Abstract
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.
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Classical phase-separating proteins such as FUS, TDP-43, tau, and α-synuclein exhibit abnormal accumulation and aggregation that are closely linked to neuronal dysfunction.
“Classical phase‐separating proteins such as FUS, 46 TDP‐43, 47 tau, 25 , 29 and α‐synuclein 48 exhibit abnormal accumulation and aggregation that are closely linked to neuronal dysfunction.”
From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [48]
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- Authors
- Ray, S., Singh, N., Kumar, R., Patel, K., Pandey, S., Datta, D., Mahato, J., Panigrahi, R., Navalkar, A., Mehra, S., Gadhe, L., Chatterjee, D., Sawner, A. S., Maiti, S., Bhatia, S., Gerez, J. A., Chowdhury, A., Kumar, A., Padinhateeri, R., Riek, R., Krishnamoorthy, G., & Maji, S. K.
- Affiliations
- Indian Institute of Technology Bombay (IN)
- Tata Institute of Fundamental Research (IN)
- ETH Zurich (CH)
- Anna University, Chennai (IN)
- Corresponding author
- Maji, Samir K.
- ORCID
- 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
- Maji, Samir K.
- Venue
- Nature Chemistry
- Published
- 2020-06-08
- Volume
- 12
- Issue
- 8
- Pages
- 705-716
- ISSN
- 1755-4330 (ISSN-L)
- 1755-4349
- OpenAlex
- W3033847448
- Cited by
- 863
- References
- 4
- Citations by year
- 2026: 176 · 2025: 183 · 2024: 142 · 2023: 130 · 2022: 116 · 2021: 85 · 2020: 27 · 2019: 4
- FWCI
- 38.17
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Chemistry (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Keywords
- alpha-synuclein, liquid-liquid phase separation, protein aggregation, amyloid fibril formation, Parkinson's disease, nucleation, droplets, aggresomes, microtubules, low pH, phosphomimetic substitution, familial Parkinson's disease mutations, oligomers
- MeSH terms
- HeLa Cells, Humans, Hydrogen-Ion Concentration, Parkinson Disease, Polyethylene Glycols, Recombinant Proteins, Mutagenesis, Site-Directed, Microscopy, Confocal, Phase Transition, alpha-Synuclein, Protein Aggregates
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