G4s Serve as a Scaffold for α-Synuclein Aggregation, Which Could Be Utilized in Drug Development

Neurodegenerative diseases triggered by excessive accumulation of the protein synuclein in the brain are collectively known as “synucleinopathies.” Parkinson’s disease, characterized by tremors in the limbs and slowed movement, is one of the most well-known examples. Although α-synuclein^*1 aggregation is widely considered a cause of Parkinson’s disease, the precise mechanism driving this aggregation had remained unclear.

This study has revealed that assemblies of G-quadruplexes (hereinafter “G4s”, Fig. 1), a higher-order RNA structure^*2, act as a scaffold that accelerates α-synuclein aggregation. In the brains of Parkinson’s disease patients, G4s coexist with nearly all α-synuclein aggregates. In synucleinopathy mouse models, inhibiting G4s assembly dramatically suppressed α-synuclein aggregation and significantly slowed the progression of motor dysfunction.

These findings show that G4s assembly acts as the starting points for α-synuclein aggregation and that inhibiting G4s assembly can effectively suppress disease progression. Furthermore, reports indicate that G4s assembly is also involved in hereditary neurodegenerative conditions distinct from Parkinson’s disease.

*1 α-synuclein
A small protein abundant in presynaptic terminals. Its aggregation leads to nerve cell damage.

*2 Higher-order RNA structures
Three-dimensional structures formed by RNA folding. The pattern determines the function.

Why Does α-Synuclein Aggregate?

Amidst a population aging trend, the number of patients with neurodegenerative diseases rises every year, making it a major social issue. Synucleinopathies, such as Parkinson’s disease and Lewy body dementia, are caused by intracellular aggregation of the protein α-synuclein. However, the precise mechanisms by which normally non-aggregating α-synuclein proteins form these aggregates had remained unclear. Unraveling this mechanism and preventing α-synuclein aggregation could significantly reduce the risk of disease onset.

G4s Drive α-Synuclein Aggregation

The research group discovered that α-synuclein binds strongly to G4s, a higher-order RNA structure, and revealed that G4s serve as a scaffold for α-synuclein aggregates. Pathological analysis of the brains of Parkinson’s disease patients showed that G4s had accumulated in approximately 90% of the observed α-synuclein aggregates. To determine if G4s could trigger α-synuclein aggregation, the team made synucleinopathy mouse models and artificially increased G4 levels in the brain. The result was that intracellular α-synuclein formed aggregates on the G4s, leading to neurodegeneration and motor dysfunction. Conversely, oral administration of 5-aminolevulinic acid, which suppresses G4s assembly, to the model mice reduced α-synuclein aggregation and significantly slowed the progression of motor dysfunction.

These findings confirm that G4s assembly is at least one key cause of α-synuclein aggregation. Moreover, G4s assembly is triggered by elevated intracellular calcium concentration caused by cellular stress. In short, this study has revealed the mechanism by which α-synuclein aggregates, as illustrated below (Fig. 2).

Applications in Drug Development for Neurodegenerative Diseases

This study has shown that G4s assembly triggers aggregation of α-synuclein. Furthermore, suppressing excessive G4s assembly prevented α-synuclein aggregation and halted the progression of motor dysfunction. The research group has previously reported that the tau protein, related to Alzheimer’s disease, also aggregates in response to G4s. Taken together, these findings strongly suggest that G4s assembly is not limited to specific diseases but is likely a common factor across multiple neurodegenerative conditions.

If drugs capable of inhibiting G4s assembly can be developed, they could slow or prevent disease progression at the pre-symptomatic stage for a wide range of neurodegenerative disorders, including synucleinopathies.