Neurons with a mutation in the tau protein gene "in vitro"
A human model of taupathies has been created
LifeSciencesToday based on Gladstone Institutes: Disease in a DishThere is no simple way to study brain diseases: extracting neurons from a living organ is a complex and risky procedure, while postmortem analysis of a patient's brain, as a rule, shows only the final stages of the disease.
Animal models, although extremely informative, often fail to meet expectations at the crucial stage – the stage of developing drugs to influence pathology. Result: we are woefully unprepared to fight this class of diseases.
However, scientists from the Gladstone Institutes and the University of California, San Francisco (UCSF) are using a potentially more effective approach: the most modern methods of cell reprogramming and genetic engineering allowed them to create a human model of one of the types of neurodegenerative diseases - taupathies in a Petri dish.
This model made it possible to identify one of the molecular processes that cause neuron degeneration – a hallmark of diseases such as Alzheimer's disease and frontotemporal dementia (FTD). The data obtained by American researchers, published in the journal Stem Cell Reports (Fong et al., Genetic Correction of Tauopathy Phenotypes in Neurons Derived from Human Induced Pluripotent Stem Cells), give scientists new tools to combat these and other deadly neurological diseases.
A research team led by Yadong Huang, MD, PhD, has identified an important mechanism underlying taupathies. Taupathies– a group of diseases that includes both Alzheimer's disease and frontotemporal dementia, are characterized by abnormal accumulation of tau protein in neurons. The accumulation of tau, according to scientists, contributes to the degeneration of nerve cells, leading to the development of severe symptoms such as dementia and memory loss. But although these ideas have long been accepted by the scientific community, the underlying molecular events remain largely unknown.
"Much about the mechanisms associated with taupathies remains a mystery, partly because traditional approaches – such as postmortem brain analysis and animal models – provide an incomplete picture," explains Dr. Huang. "But using the most modern methods of working with stem cells, we obtained neurons in a Petri dish that showed the same pattern of degeneration and cell death as in the brains of patients. Studying this model for the first time allowed us to see how certain genetic mutations can trigger the development of taupathies."
Neurons (colored red) carrying a genetic mutation that makes them predisposed to degeneration. They are obtained from the skin cells of an adult patient with frontotemporal degeneration. Their genome exactly corresponds to the genome of the patient's cells, and they can be used as a model of this disease. (Photo: Helen Fong/Yadong Huang)It has recently been established that this mutation in the tau protein gene can increase the risk of developing various taupathies, including Alzheimer's disease and frontotemporal degeneration.
Dr. Huang, in collaboration with the head of the UCSF Memory and Aging Center Bruce Miller, MD, who provided the skin cells of patients with this mutation, reprogrammed them into induced pluripotent stem cells (iPSCs) using a method developed by Shinya Yamanaka, MD, PhD, a 2012 Nobel Prize-winning researcher at the Gladstone Institute. Induced pluripotent stem cells, almost indistinguishable from the so-called embryonic stem cells, can develop into almost any cell in the body.
Yamanaka technology was used in combination with the latest gene editing method, which made it possible to remove this mutation in part of the IPSC. As a result, a system was obtained that made it possible to compare neurons carrying this mutation with neurons that do not have it.
"Our approach allowed us to grow human neurons in a Petri dish with exactly the same mutation as in the neurons of the patients' brains," says the first author of the article, Helen Fong, PhD, postdoctoral fellow at the California Institute for Regenerative Medicine. "Comparing diseased neurons with "genetically corrected" healthy ones, we could observe – cell by cell –how a mutation in tau leads to its abnormal accumulation and, over time, to degeneration and death of neurons."
"The main function of tau protein is to maintain the structure of the cytoskeleton of neurons and regulate neuronal activity," Dr. Huang continues. "But our study showed that the tau produced by the neurons of patients with this mutation is different from normal; therefore, it is labeled by the cell to become a target that needs to be destroyed. However, instead of being removed from the cell, such a tau is cut into pieces. Over time, these potentially toxic fragments accumulate and can indeed cause degradation and death of a neuron."
However, after correcting this mutation, scientists removed the "death mark" from tau. The protein remained intact, its abnormal accumulation stopped, and the neurons showed no signs of degeneration. Ongoing research is aimed at determining whether abnormal fragmentation and accumulation of mutant tau are the main cause of neuronal death and, if so, how to block these processes.
The search for a way to block the accumulation of toxic tau fragments is one of the key directions in the development of medicines, but so far it has not been crowned with success. However, Dr. Huang and his colleagues consider their approach to be exactly what scientists need to combat taupathies, and are optimistic.
"The data we have obtained not only gives an idea of how these powerful new models can shed light on the mechanisms of the disease," concludes Dr. Miller. "They can also be invaluable for screening potential drugs for more effective treatment of Alzheimer's disease, frontotemporal degeneration and related diseases."
Portal "Eternal youth" http://vechnayamolodost.ru17.09.2013