Liquid-liquid phase separation and liquid-to-solid transition mediate α-synuclein amyloid fibril containing hydrogel formation
Liquid-liquid phase separation and liquid-to-solid transition mediate α-synuclein amyloid fibril containing hydrogel formation
SUMMARY α-Synuclein (α-Syn) aggregation and amyloid formation is directly linked with Parkinson’s disease (PD) pathogenesis. However, the early events involved in this process remain unclear. Here, using in vitro reconstitution and cellular model, we show that liquid-liquid phase separation (LLPS) 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 amyloid-hydrogel containing oligomers and fibrillar species. Factors known to aggravate α-Syn aggregation such as low pH, phosphomimic substitution, and familial PD mutation also promote α-Syn LLPS and its subsequent maturation. We further demonstrate α-Syn liquid droplet formation in cells, under oxidative stress. These cellular α-Syn droplets eventually transform into perinuclear aggresomes, the process regulated by microtubules. The present work provides detailed insights into the phase separation behavior of natively unstructured α-Syn and its conversion to a disease-associated aggregated state, which is highly relevant in PD pathogenesis.
Krishnamoorthy G、Pandey Satyaprakash、Maiti Siddhartha、Bhatia Sandhya、Singh Ajay、Maji Samir K、Ray Soumik、Singh Nitu、Gadhe Laxmikant、Mahato Jaladhar、Patel Komal、Kumar Ashutosh、Navalkar Ambuja、Chatterjee Debdeep、Padinhateeri Ranjith、Chowdhury Arindam、Gerez Juan、Mehra Surabhi、Panigrahi Rajlaxmi、Kumar Rakesh、Riek Roland、Datta Debalina
Department of Biotechnology, Anna UniversityDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayNational Center for Biological Sciences, Tata Institute of Fundamental ResearchDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Chemistry, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Chemistry, IIT BombayDepartment of Chemistry and Applied BiosciencesDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Biosciences and Bioengineering, IIT BombayDepartment of Chemistry and Applied BiosciencesDepartment of Biosciences and Bioengineering, IIT Bombay
神经病学、精神病学基础医学生物科学研究方法、生物科学研究技术
Krishnamoorthy G,Pandey Satyaprakash,Maiti Siddhartha,Bhatia Sandhya,Singh Ajay,Maji Samir K,Ray Soumik,Singh Nitu,Gadhe Laxmikant,Mahato Jaladhar,Patel Komal,Kumar Ashutosh,Navalkar Ambuja,Chatterjee Debdeep,Padinhateeri Ranjith,Chowdhury Arindam,Gerez Juan,Mehra Surabhi,Panigrahi Rajlaxmi,Kumar Rakesh,Riek Roland,Datta Debalina.Liquid-liquid phase separation and liquid-to-solid transition mediate α-synuclein amyloid fibril containing hydrogel formation[EB/OL].(2025-03-28)[2025-04-30].https://www.biorxiv.org/content/10.1101/619858.点此复制
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