summary: Researchers have identified unique RNA structures called G-quadruplexes (G4) that promote the aggregation of the harmful alpha-synuclein protein associated with neurodegenerative diseases like Parkinson’s disease. Elevated calcium levels induce these G4s, which act as “scaffolds” for α-synuclein aggregation. Administration of 5-aminolevulinic acid (5-ALA) to model mice prevented aggregation and reduced motor symptoms.
This breakthrough suggests that G4-targeted therapy may provide early intervention in neurodegenerative diseases. This finding may also apply to other conditions that involve protein aggregation, such as Alzheimer’s disease, potentially expanding the potential impact of these treatments. Overall, this study represents a major step forward in neurodegeneration research and treatment development.
Important facts:
- G-quadruplex (G4) RNA structures promote aggregation of α-synuclein, a factor in neurodegeneration.
- 5-Aminolevulinic acid (5-ALA) inhibits G4 formation and prevents harmful aggregation.
- This finding suggests that G4 regulation is a potential therapeutic target for neurodegenerative diseases.
sauce: Kumamoto University
A research team at Kumamoto University has elucidated the mechanism behind the formation of harmful protein aggregates that cause neurodegenerative diseases such as Parkinson’s disease.
A research team led by Professor Norifumi Shioda and Associate Professor Yasushi Yasushi Yasushi Yasushi found that a unique RNA structure called G-quadruplex (G4) plays a central role in promoting the aggregation of alpha-synuclein, a protein associated with neurodegeneration. This was identified for the first time.
The research will be published in a journal cell.
By demonstrating that inhibiting G4 assembly can potentially prevent the development of synucleinopathies, this discovery positions G4 as a promising target for early intervention in these diseases. .
In healthy conditions, alpha-synuclein normally regulates neural function. However, in neurodegenerative diseases, it aggregates and causes cell damage and motor symptoms.
The researchers identified that G4, a four-stranded RNA structure that forms in response to cellular stress, acts as a “scaffold” that promotes alpha-synuclein aggregation.
Elevated calcium levels, common under stress, trigger G4 assembly, which subsequently attracts alpha-synuclein and converts it into a state prone to harmful aggregation.
The team went a step further and demonstrated a new approach to preventing this process. They administered 5-aminolevulinic acid (5-ALA), a compound that inhibits G4 formation, to a mouse model that exhibits Parkinson’s disease-like symptoms.
Impressively, 5-ALA treatment not only prevented α-synuclein aggregation but also halted the progression of motor symptoms. This is a promising sign for potential treatments targeting early stages of neurodegeneration.
This breakthrough has the potential to significantly advance therapeutics targeting neurodegenerative diseases by focusing on G4 regulation. This discovery could extend the impact of such treatments beyond Parkinson’s disease, as G4 is also involved in other diseases such as Alzheimer’s disease.
These findings shed new light on preemptive strategies to combat neurodegeneration and improve quality of life in older adults.
About this genetics and Parkinson’s disease research news
author: Yasushi Yabuki
sauce: Kumamoto University
contact: Yasushi Yabuki – Kumamoto University
image: Image credited to Neuroscience News
Original research: Open access.
“RNA G-quadruplexes form a scaffold that promotes neuropathological α-synuclein aggregation” Written by Yasushi Yasushi et al. cell
abstract
RNA G-quadruplexes form a scaffold that promotes neuropathological α-synuclein aggregation
Synucleinopathies such as Parkinson’s disease, Lewy body dementia, and multiple system atrophy are caused by aggregation of α-synuclein, leading to progressive neurodegeneration.
However, the mechanism of intracellular α-synuclein aggregation remains unclear.
Here we demonstrate that RNA G-quadruplex assemblies form a scaffold for α-synuclein aggregation and contribute to neurodegeneration. Purified α-synuclein binds directly to RNA G-quadruplexes via its N-terminus.
RNA G quadruplex receives Ca2+Phase separation and assembly accelerates the sol-gel phase transition of α-synuclein.
In fibril-processed neurons preformed with α-synuclein, excess cytosolic Ca causes RNA G-quadruplex assemblies containing synaptic mRNAs to coaggregate with α-synuclein.2+ influx and cause synaptic dysfunction.
Forced RNA G-quadruplex assembly using an optogenetic approach causes α-synuclein aggregation, leading to neuronal dysfunction and neurodegeneration.
Administration of 5-aminolevulinic acid, a protoporphyrin IX prodrug, prevented RNA G-quadruplex phase separation and thereby inhibited α-synuclein in synucleinopathic mice injected with α-synuclein preformed fibrils. Reduces aggregation, neurodegeneration, and progressive movement disorders.
Therefore, Ca2+ Influx-induced RNA G-quadruplex assembly promotes α-synuclein phase transition and aggregation and may contribute to synucleinopathy.
