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 AS, Maiti S, Bhatia S, Gerez JA, Chowdhury A, Kumar A, Padinhateeri R, Riek R, Krishnamoorthy G, Maji SK. α-Synuclein aggregation nucleates through liquid-liquid phase separation. Nat Chem. 2020 Aug;12(8):705-716. Epub 2020 Jun 8 PubMed.
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Comments
MPI-CBG
This is a very nice paper. It establishes that liquid-like states of α-synuclein promote the assembly of amyloid-like aggregates and that there are various physical chemical factors such as pH and metal ions that shift the equilibrium toward liquid droplet formation. This has previously been shown for various RNA-binding proteins and the microtubule-associated protein tau, so more and more we are seeing that this is a general mechanism. The high protein concentration in the liquid droplets presumably promotes the formation of a nucleus that then grows into amyloid fibrils. More generally, we are gaining insight into how protein aggregation diseases arise, and this may help us identify factors and small molecules that can inhibit this step.
Van Andel Research Institute
In the etiopathogenesis of synucleinopathies, there is a substantial gap in our understanding of how and when α-synuclein de novo assembles into insoluble aggregates. Genetic and environmental factors have provided strong links between α-synuclein and disease development, but it is unclear how we can tie together a triggering event with the accumulation of α-synuclein and, eventually, pathogenesis. Ray and colleagues propose the idea that under altered or pathogenic conditions, α-synuclein can undergo liquid-liquid phase separation (LLPS) and form a dynamic droplet with a mixture of aggregated assemblies that progressively develops into a solidifying aggresome. All this happens with relatively fast kinetics.
This has several intriguing implications, certainly if we consider the role of α-synuclein in the peripheral immune system or the enteric nervous system, where the protein is continuously exposed to an environment that can rapidly change. Only by adding metals, or by altering lipid composition, does α-synuclein undergo LLPS at physiological relevant levels.
A triggering event, such as changes in the microbiome, could affect local homeostasis and change iron and copper concentrations, which in turn could cause α-synuclein to undergo LLPS or liquid-to-solid transition. If these assemblies are fragmented or released from the mature aggresome, it would be interesting to see if they can seed propagation to (or within) the central nervous system. Future research will have to show what type of assemblies are formed in response to a trigger, how its aggregation into droplets could be facilitated by other PD risk factors, and how they can potentially impact different types of synucleinopathies.
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