RNA scaffold drives alpha-synuclein protein clumping in neurons

G4s may be targets for early Parkinson’s intervention, mouse study suggests

by Margarida Maia, PhD | November 8, 2024

A type of RNA structure called G-quadruplex, or G4 — a four-stranded RNA structure that forms when calcium enters cells in response to stress — may offer a scaffold for the alpha-synuclein protein to clump together and become toxic to nerve cells in Parkinson’s disease, research suggests.

In a mouse model of Parkinson’s in which alpha-synuclein is seeded into the brain and allowed to form toxic clumps, oral treatment with an inhibitor of G4 scaffolding called 5-ALA eased neurodegeneration and motor symptoms that are characteristic of the disease, researchers at Kumamoto University found.

While it’s still early to know whether these findings will translate to humans, they position G4s as targets for early intervention. Because G4s also appear to play a role in other neurodegenerative diseases, such as Alzheimer’s, the findings may be relevant beyond Parkinson’s, according to a university press release.

An “extremely low-toxic and blood-brain barrier-permeable [molecule],” meaning it can cross from the bloodstream into the brain, 5-ALA could offer benefits as prophylaxis or preventive treatment, the researchers wrote in the study, “RNA G-quadruplexes form scaffolds that promote neuropathological [alpha]-synuclein aggregation,” published in Cell.

In Parkinson’s, misfolding makes the alpha-synuclein protein prone to clumping into threadlike structures called fibrils. These fibrils assemble into Lewy bodies, which accumulate within nerve cells and cause dopaminergic neurons to die. These neurons produce dopamine, a chemical involved in motor control.

What exactly drives alpha-synuclein into clumping is unclear. In the study, researchers identified G4s as structures that can attract alpha-synuclein and cause it to transition into clumps.

G4s form when high amounts of calcium enter cells under stress, causing RNA, a messenger molecule that helps translate genetic information from DNA to proteins, to stack into four-stranded structures.

When researchers added preformed alpha-synuclein fibrils to lab-grown neurons, G4s and alpha-synuclein came together to form clumps, which interfered with how well neurons were able to communicate with each other.

To confirm that G4s offer a scaffold for the alpha-synuclein protein, the team used light (optogenetics) to induce G4s formation within neurons. In neurons containing G4s responsive to blue light, alpha-synuclein formed clumps that remained stable even after the light was turned off, indicating that the clumping was irreversible.

When tested in mice, the use of this optogenetics system resulted in the death of dopaminergic neurons and motor symptoms similar to those of Parkinson’s. These findings suggests that, once formed, G4s may drive the alpha-synuclein protein into clumping, causing neurodegeneration.

The researchers used a compound called 5-aminolevulinic acid, or 5-ALA, to inhibit the formation of G4s.

In mice in which Parkinson’s was induced by injection of preformed alpha-synuclein fibrils into the brain, daily treatment with an oral solution of 5-ALA reduced alpha-synuclein clumping and loss of dopaminergic neurons. After two months of treatment, the team also observed improved motor function compared with untreated mice.

“Orally administered 5-ALA can act on the brain … without serious adverse effects,” the researchers wrote. “Moreover, 5-ALA can be prophylactically administered before progressive motor dysfunction and therefore could be a promising agent for the management of neurodegenerative diseases.”