A team of researchers from Kumamoto University has discovered a groundbreaking mechanism in the formation of harmful protein aggregates that lead to neurodegenerative diseases such as Parkinson’s disease. The team, led by Professor Norifumi Shioda and Associate Professor Yasushi Yabuki, has identified for the first time that unique RNA structures called G-quadruplexes (G4s) play a central role in promoting the aggregation of α-synuclein, a protein that is associated with neurodegeneration. By demonstrating that inhibiting G4 assembly could potentially prevent the onset of synucleinopathies, this discovery positions G4 as a promising target for early intervention in these diseases.
In a healthy state, α-synuclein typically regulates neuronal function. However, in neurodegenerative diseases it accumulates, leading to cell damage and motor symptoms. The researchers identified that G4s, four-stranded RNA structures that form in response to cellular stress, function as a “scaffold” that facilitates the aggregation of α-synuclein. Elevated calcium levels, often seen under stress, trigger G4 assembly, which then recruits α-synuclein, converting it to a damaging, aggregate-prone state.
The team went one step further and demonstrated a new approach to prevent this process. They administered 5-aminolevulinic acid (5-ALA), a compound that blocks G4 formation, to model mice exhibiting Parkinson’s-like symptoms. Impressively, 5-ALA treatment not only prevented α-synuclein aggregation but also halted the progression of motor symptoms, a promising sign for potential therapies targeting early-stage neurodegeneration.
This breakthrough could significantly advance treatments targeting neurodegenerative diseases by focusing on G4 regulation. Because G4s are also involved in other diseases such as Alzheimer’s disease, this discovery could expand the impact of such treatments beyond Parkinson’s disease. These findings were published in the journal Cell on October 18, 2024, shedding new light on preventive strategies to combat neurodegeneration and improve the quality of life in the aging population.
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Magazine reference:
Matsuo, K., et al. (2024). RNA G-quadruplexes form scaffolds that promote neuropathological α-synuclein aggregation. Cell. doi.org/10.1016/j.cell.2024.09.037.