Research Papers

The miracle molecule that rejuvenates the brain, ISRIB

2021-12-13 21:24

The miracle molecule that could treat brain injuries and boost your fading memory

It is becoming clear that a molecule discovered by chance more than 10 years ago can treat Alzheimer's disease and traumatic brain injury. This molecule, now called "ISRIB," may also improve cognitive function in healthy people.

Carmela Sidlauski had no intention of looking for a miracle drug. Professor Peter Walter's lab at the University of California, San Francisco, has equipment that can automate experiments and run them at high speed, where she was testing thousands of molecules. She picked up a molecule from what was rejected in the test and decided to investigate further. I was interested in some of the power it had.

That was 2010. Now, summarizing future applications in the medical field, this molecule seems to be an incredibly promising strain. After Sidlauski decided to investigate further, the molecule showed recovery of memory formation in mice months after traumatic brain injury. It is also known that it has the potential to treat neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and ALS (also known as amyotrophic lateral sclerosis or Lou Gehrig's disease). Not only that, it seems that the decline in cognitive function associated with aging can be alleviated. It also gives healthy animals (at least for mice) memory comparable to video memory.

Sidlauski believes that the reason why this molecule has such a variety of effects is that it is involved in the treatment of stress caused by physical trauma and nervous system diseases on the brain. When the above problems occur in the body, the brain stops cognitive functions such as memory formation in order to protect itself. This newly discovered molecule reverses it. "I didn't find it because I wanted to find it. I just happened to find it," says Sidlauski. "But it's exciting to think that we have new ways to control the pathways that may be the root of a variety of pathologies."

Can this molecule also restore human cognitive function? I don't know yet. So far, most of the research has been on mice and human cells placed in Petri dishes. But the details will soon be known. In 2015, Silicon Valley-based biotechnology company Calico Labs licensed the molecule. Calico Lab is a company founded by the founders of Google for the purpose of drug discovery based on the biology of aging. Kariko Lab has hired Sidlauski as Principal Investigator to work on the application of this molecule in the treatment of a variety of diseases, including ALS, Parkinson's disease, and traumatic brain injury. In February, we will begin a human safety study of the first drug candidate for neurodegenerative diseases developed based on this molecule, and will start research on ALS patients later this year. Has been announced. Drug candidates for Parkinson's disease and traumatic brain injury are likely to be announced in the future.

The completion of these medicines may be a long way off (most candidates do not go through early clinical trials), but early results have recently been achieved by Professor Walter and researchers around the world. Coupled with the research, it convinced the shocking hypothesis. Genetic disorders such as traumatic brain injury, Alzheimer's disease, and even Down's syndrome cause serious cognitive problems not because of the disease, genetic factors, or the trauma itself, but how the cells deal with such stress. It is a hypothesis that there is.

Researched by Professor Sidlauski and Professor Walter, this molecule, now called "ISRIB," works by modifying the major pathways within neurons to regulate the rate at which mouse cells synthesize new proteins. I understand. The synthesis of new proteins is an essential process for memory formation and learning. A study by Professor Walter and colleagues reveals that when cells are exposed to stress, protein synthesis can stop completely. The Sidlauski molecule is thought to have a beautifully simple mechanism to restore it.

If this works for humans, the potential for medical applications is immeasurable and widespread. Cognitive problems caused by a wide variety of causes may be solved simply by fine-tuning the cellular response. But there are also dangers. Manipulating such a fundamental process also carries the risk of causing unintended and harmful changes.

"We need to know if there are any side effects," said Arun Asok, a neuroscientist at Columbia University who specializes in memory (not involved in this study). "But there is a demand for these medicines. It may save many people suffering from illnesses for which there are currently few cures."

Stress stops protein synthesis

Memory is like a constellation unique to a person, which is a combination of sensory experiences and thoughts that emerge when one looks back on the past. The theory that that memory is somehow encoded in the numerous connections between the neurons that make up the human brain has existed since the dawn of neuroscience.

It is now known that protein synthesis plays an important role in this process. The proteins that connect neurons are also the materials needed to imprint experience on the brain. In fact, studies in the 1960s have shown that chemically interfering with protein synthesis prevents the formation of new memories.

Professor Walter said in the 1980s and 90s, when unfolded or unfolded proteins were detected intracellularly (which is characteristic of neurodegenerative diseases), until the problem was resolved. It has been shown that something like an emergency stop device that stops all synthesis works. This phenomenon, which Professor Walter called "Unfolded Protein Response (UPR)," is similar to sounding an emergency alert and stopping work in a busy workplace. After the stop, the cell repairer gathers at the scene to try to fix the problem, and finally orders the cell to commit suicide if it can't be helped.

Shortly thereafter, other researchers discovered that somatic cell protein synthesis was suspended for a variety of factors, in addition to proteins that were not properly folded. There are many stressors that can activate protein production line shutdown devices, such as starvation, viral infections, physical damage to cell structures, and oxidative stress commonly found in aged cells. In fact, it has been found that disruption of metabolic function can almost certainly stop protein synthesis and induce cell death. Over time, other researchers named the symptoms that included Walter's endoplasmic reticulum stress response.

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