The aberrant aggregation of the presynaptic protein α-synuclein (α-syn) is a hallmark of synucleinopathies, which include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. Previous studies have suggested that α-syn can undergo liquid–liquid phase separation (LLPS) and transition from a liquid to a solid state, which contributes to aggregation and fibril formation. However, the factors that instigate α-syn LLPS have remained unclear. Now, Matsuo et al. have discovered that the cytoplasmic Ca2+ influx triggers the assembly of RNA G-quadruplexes (rG4s), which bind to α-syn and facilitate its LLPS and gelation.

The team also developed a light-induced assembly system called optoG4. This system includes an RNA component with rG4-forming repeats and MS2 RNA hairpin repeats, and a protein component that combines the MS2-binding protein MCP with mCherry and CRY2, a protein capable of oligomerization upon exposure to blue light. Using the optoG4 system, the team were able to control the formation and dissolution of rG4 condensates in cultured neurons and in mice. They observed that rG4 assembly led to the aggregation of endogenous α-syn and induced Parkinson’s disease-like phenotypes, such as neuron death and motor dysfunction. Furthermore, oral administration of 5-aminolevulinic acid, a prodrug of protoporphyrin IX that binds to rG4, reduced α-syn aggregation and alleviated Parkinson’s disease-like phenotypes in mice treated with α-syn preformed fibrils.