Scientists have discovered an additional potential cause of the genetic mutations that result in rare conditions such as Huntington’s disease (HD). The neurodegenerative diseases, which also include most spinocerebellar ataxias (SCAs), are known to be caused by an expansion in the CAG (cytosine-adenine-guanine) repeats within a gene that in turn leads to an expanded polyglutamine (polyQ) tract in a protein.
Such diseases are inherited, given that the expansion of CAG repeats in a gene can be passed down the generations. Previously, it had been thought the damage in these genetic diseases was caused solely by increased protein aggregate toxicity. However, a new study “Gelation of cytoplasmic expanded CAG RNA repeats suppresses global protein synthesis” in Nature Chemical Biology has found an additional source, i.e., RNA, that can generate the levels of toxicity to cause damage to the brain in these diseases.
The research has revealed that expanded CAG repeat RNA can form RNA aggregates in the cytoplasm through a process known as liquid-liquid phase separation and gelation. This reduces global protein synthesis and leads to neurotoxicity and neurodegeneration.
“RNA molecules with the expanded CAG repeat (eCAGr) may undergo sol–gel phase transitions, but the functional impact of RNA gelation is completely unknown. Here, we demonstrate that the eCAGr RNA may form cytoplasmic gel-like foci that are rapidly degraded by lysosomes,” write the investigators.
“These RNA foci may significantly reduce the global protein synthesis rate, possibly by sequestering the translation elongation factor eEF2. Disrupting the eCAGr RNA gelation restored the global protein synthesis rate, whereas enhanced gelation exacerbated this phenotype. eEF2 puncta were significantly enhanced in brain slices from a knock-in mouse model and from patients with Huntington’s disease, which is a CAG expansion disorder expressing eCAGr RNA.
“Finally, neuronal expression of the eCAGr RNA by adeno-associated virus injection caused significant behavioral deficits in mice. Our study demonstrates the existence of RNA gelation inside the cells and reveals its functional impact, providing insights into repeat expansion diseases and functional impacts of RNA phase transition.”
Ongoing international collaboration
The study is part of an ongoing international collaboration between experts in neuroscience and genetics from the University of Plymouth (U.K.), Fudan University, and Tsinghua University (China). The authors say it significantly advances the knowledge available to those working to understand the cause of such inherited conditions. They are also now planning to conduct further research to fully address the implication of expanded-CAG repeats RNA aggregate toxicity in patients.
The research was co-led by Shouqing Luo, PhD, professor of neurobiology at the University of Plymouth, and an expert in HD and other neurodegenerative diseases.
“Conditions such as Huntington’s disease currently have few treatments and no known cure. If we are to make the significant steps needed to directly benefit patients and their families, we need to fully understand the nature of the conditions we are dealing with,” said Luo.
“This study marks a real step forward in what we know about the causes of Huntington’s disease and other neurodegenerative conditions. It provides us with new mechanistic insights into diseases such as HD and SCAs that we can potentially use in the future to develop more effective ways of treating these conditions.”
Luo’s work primarily focuses on establishing the processes through which HD develops and using that knowledge to find new ways of treating it and other diseases, including dementia. His team has previously shed light on the mechanisms behind a process through which cells work to destroy bacteria and viruses after infection (autophagy) and how it progresses.
Luo has also established ways of facilitating the autophagy process, which results in the mutant huntingtin (HTT) protein in brain cells that causes HD to be removed.