Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation
The Lewy bodies and Lewy neurites are key pathological hallmarks of Parkinson’s disease (PD). Single-point mutations associated with familial PD cause α-synuclein (α-Syn) aggregation, leading to the formation of Lewy bodies and Lewy neurites. Recent studies suggest α-Syn nucleates through liquid–liq...
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MDPI AG
2023-04-01
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| author | Bingkuan Xu Fengshuo Fan Yunpeng Liu Yinghui Liu Lin Zhou Haijia Yu |
| author_facet | Bingkuan Xu Fengshuo Fan Yunpeng Liu Yinghui Liu Lin Zhou Haijia Yu |
| author_sort | Bingkuan Xu |
| collection | DOAJ |
| description | The Lewy bodies and Lewy neurites are key pathological hallmarks of Parkinson’s disease (PD). Single-point mutations associated with familial PD cause α-synuclein (α-Syn) aggregation, leading to the formation of Lewy bodies and Lewy neurites. Recent studies suggest α-Syn nucleates through liquid–liquid phase separation (LLPS) to form amyloid aggregates in a condensate pathway. How PD-associated mutations affect α-Syn LLPS and its correlation with amyloid aggregation remains incompletely understood. Here, we examined the effects of five mutations identified in PD, A30P, E46K, H50Q, A53T, and A53E, on the phase separation of α-Syn. All other α-Syn mutants behave LLPS similarly to wild-type (WT) α-Syn, except that the E46K mutation substantially promotes the formation of α-Syn condensates. The mutant α-Syn droplets fuse to WT α-Syn droplets and recruit α-Syn monomers into their droplets. Our studies showed that α-Syn A30P, E46K, H50Q, and A53T mutations accelerated the formation of amyloid aggregates in the condensates. In contrast, the α-Syn A53E mutant retarded the aggregation during the liquid-to-solid phase transition. Finally, we observed that WT and mutant α-Syn formed condensates in the cells, whereas the E46K mutation apparently promoted the formation of condensates. These findings reveal that familial PD-associated mutations have divergent effects on α-Syn LLPS and amyloid aggregation in the phase-separated condensates, providing new insights into the pathogenesis of PD-associated α-Syn mutations. |
| first_indexed | 2024-03-11T03:55:04Z |
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| last_indexed | 2024-03-11T03:55:04Z |
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| spelling | doaj.art-bbab2f6f6a634dcf878991c98b92e7842023-11-18T00:38:15ZengMDPI AGBiomolecules2218-273X2023-04-0113572610.3390/biom13050726Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid AggregationBingkuan Xu0Fengshuo Fan1Yunpeng Liu2Yinghui Liu3Lin Zhou4Haijia Yu5Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, ChinaSchool of Chemistry and Bioengineering, Nanjing Normal University Taizhou College, Taizhou 225300, ChinaJiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing 210023, ChinaThe Lewy bodies and Lewy neurites are key pathological hallmarks of Parkinson’s disease (PD). Single-point mutations associated with familial PD cause α-synuclein (α-Syn) aggregation, leading to the formation of Lewy bodies and Lewy neurites. Recent studies suggest α-Syn nucleates through liquid–liquid phase separation (LLPS) to form amyloid aggregates in a condensate pathway. How PD-associated mutations affect α-Syn LLPS and its correlation with amyloid aggregation remains incompletely understood. Here, we examined the effects of five mutations identified in PD, A30P, E46K, H50Q, A53T, and A53E, on the phase separation of α-Syn. All other α-Syn mutants behave LLPS similarly to wild-type (WT) α-Syn, except that the E46K mutation substantially promotes the formation of α-Syn condensates. The mutant α-Syn droplets fuse to WT α-Syn droplets and recruit α-Syn monomers into their droplets. Our studies showed that α-Syn A30P, E46K, H50Q, and A53T mutations accelerated the formation of amyloid aggregates in the condensates. In contrast, the α-Syn A53E mutant retarded the aggregation during the liquid-to-solid phase transition. Finally, we observed that WT and mutant α-Syn formed condensates in the cells, whereas the E46K mutation apparently promoted the formation of condensates. These findings reveal that familial PD-associated mutations have divergent effects on α-Syn LLPS and amyloid aggregation in the phase-separated condensates, providing new insights into the pathogenesis of PD-associated α-Syn mutations.https://www.mdpi.com/2218-273X/13/5/726α-synucleinmutationphase transitionamyloid aggregationliquid–liquid phase separation (LLPS)Parkinson’s disease (PD) |
| spellingShingle | Bingkuan Xu Fengshuo Fan Yunpeng Liu Yinghui Liu Lin Zhou Haijia Yu Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation Biomolecules α-synuclein mutation phase transition amyloid aggregation liquid–liquid phase separation (LLPS) Parkinson’s disease (PD) |
| title | Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation |
| title_full | Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation |
| title_fullStr | Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation |
| title_full_unstemmed | Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation |
| title_short | Distinct Effects of Familial Parkinson’s Disease-Associated Mutations on α-Synuclein Phase Separation and Amyloid Aggregation |
| title_sort | distinct effects of familial parkinson s disease associated mutations on α synuclein phase separation and amyloid aggregation |
| topic | α-synuclein mutation phase transition amyloid aggregation liquid–liquid phase separation (LLPS) Parkinson’s disease (PD) |
| url | https://www.mdpi.com/2218-273X/13/5/726 |
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