The production of glycine-rich RNA-binding proteins, such as CIRBP and RBM3, upon cooling was first discovered in the 1990s. Despite evolutionary conservation and severe temperature sensitivity, the mechanism of basic cold-induced RBM3 expression remains unknown. Their discovery of temperature-regulated alternative splicing with nonsense-mediated decay (NMD) provides a universal method for controlling temperature-dependent gene expression.Â
The NMD process identifies mRNA isoforms with premature termination codons (PTCs). It targets them for breakdown, allowing for splicing-controlled gene expression regulation.
Neurodegenerative diseases are becoming more common in the aging population, and there are currently no disease-modifying medications available. Although therapeutic hypothermia increases the expression of the cold-shock protein RBM3, systemic cooling offers a health concern. A new study shows a toxic exon within the RBM3 molecule responsible for its cold-induced term.
The discovery is an important step toward harnessing the protective properties of chilling the brain to treat patients with acute brain injury and to prevent dementias like Alzheimer’s.Â
When the body cools down significantly, it produces more RBM3, a molecule known as the cold shock protein. This protein protects the brain from injury while allowing it to create new connections during hibernation.
Professor Giovanna Mallucci and colleagues demonstrated in 2015 that RBM3 could protect the brain from damage caused by a buildup of misfolded proteins, which can lead to various forms of dementia such as Alzheimer’s and Parkinson’s disease, as well as prion diseases such as Creutzfeldt-Jakob disease. (CJD).
Patients in intensive care units, particularly newborns and those with catastrophic brain injuries, are treated with induced hypothermia, in which the patients are put into comas and have their brains cooled to prevent harm. But there are risks associated with it, like blood clotting and pneumonia.
Could the cold shock protein be used to treat patients without cooling their bodies, providing a more secure method of treating severe brain injuries or a technique to shield the brain against dementia?
Scientists studied whether a form of gene therapy known as antisense oligonucleotides (ASOs) could increase levels of the cold shock protein in the brains of mice – and hence protect them.
The researchers examined the gene coding for the cold shock protein and discovered that it contains a critical region that prevents it from being expressed under normal conditions. Removing, or ‘dialing down,’ the element with an ASO resulted in a long-term increase in RBM3 production.
To see if this method could protect the brain, mice infected with prions were given a single dosage of ASO three weeks later, whereas the others received a control treatment.
The mice who received the control therapy succumbed to prion disease twelve weeks after receiving the prions and displayed severe loss of neurons in the hippocampus, a part of the brain that is important to memory.
The story was totally different for the mice who had gotten the ASO. At the same time, the other mice died from prion disease. The ASO-treated mice had RBM3 levels that were twice as high.
Neurons were preserved in seven of the eight ASO-treated mice.
Professor Giovanna Mallucci led the work at the UK Dementia Research Institute at the University of Cambridge, said, “Essentially, the cold shock protein enables the brain to protect itself – in this case, against the damage to nerve cells in the brain during prion disease. Remarkably, we showed that just a single injection with the ASO was sufficient to provide long-lasting protection for these mice, preventing the inevitable progression of neurodegeneration.”
Professor Florian Heyd of Freie Universität Berlin said, “We are still a long way off this stage as our work was in mice, but if we can safely use ASOs to boost production of the cold shock protein in humans, it might be possible to prevent dementia. We are already seeing ASOs being used to successfully treat spinal muscular atrophy and have recently been licensed to treat motor neuron disease.”
He stated that this approach has the potential to protect against diseases such as Alzheimer’s and Parkinson’s disease, for which there are currently no reliable preventative medicines.
If the findings are replicated in humans, this approach could have far-reaching implications for the treatment of patients other than those suffering from neurodegeneration, such as those suffering from hypoxia in newborn babies, heart surgery, stroke, and head injury in adults who would otherwise be treated with therapeutic hypothermia.
The Freie Universität Berlin and the UK Dementia Research Institute funded the research.
Journal Reference:
- Preußner, M et al. ASO targeting temperature-controlled RBM3 poison exon splicing prevents neurodegeneration in vivo.EMBO Molecular Medicine. DOI: 10.15252/emmm.202217157