小鼠模型实验,神经退行性疾病 z-bo 2020-11-05 328

　　Recently, researchers from the University of Utah School of Medicine in the United States explained a long-standing question: What role do mitochondria play in debilitating and fatal motor neuron diseases? They prepared a new mouse model to study this type of disease.

　　The research team led by professor of biochemistry Janet Shaw found that when healthy and functional mitochondria cannot move along axons (the cell body of nerve cells grows protrusions, the function is to transmit the action potential of the cell body to the synapses), the mice will Shows symptoms of neurodegenerative disease. Related research results were published in the recent "PNAS" journal. In the study, Shaw and colleagues said that their findings indicate that motor neuron disease may be caused by poor distribution of mitochondria along the spinal cord and axons. The first author of this article, Tammy T. Nguyen, is an MD/Ph.D medical student at the University of Utah School of Medicine. The project aims to train doctors with excellent clinical skills and rigorous scientific training, link clinical medicine with basic research, and improve health care.

　　Shaw said: “We have known the connection between mitochondrial function and distribution and neurological diseases for a long time. But we don’t know whether the defect occurs because the mitochondria cannot reach the correct position or because they cannot function properly.”

　　Mitochondria are organelles in cells that perform a variety of functions, including the production of ATP, which the cell converts into chemical energy for survival. Therefore, mitochondria are often called "cellular energy factories". They play a key role in preventing excessive calcium accumulation in cells, which can cause cell apoptosis.

　　For mitochondria to perform their functions, they must be distributed to cells in the body. This is done with the help of small protein "motors" (which transport organelles along axons). For small protein "motors" to transport mitochondria, an enzyme called mitochondrial Rho (Miro1) GTPases takes action to attach mitochondria to motor proteins. To study the connection between mitochondrial movement and motor neuron disease, Nguyen created two mouse models in which the gene that produces Miro1 was knocked out. The first mouse model lacks Miro1 in the embryonic stage. The second mouse model lacks this enzyme in the cerebral cortex, spinal cord, and hippocampus.

　　Researchers have discovered that mice lacking Miro1 during the embryonic stage have motor neuron defects that prevent them from breathing at birth. After testing the mice, Nguyen, Shaw and their colleagues found that the neurons needed to breathe were missing in the upper half of their brainstem after the mice were born. The phrenic nerve, which is also important for breathing, is also underdeveloped. Shaw said: "We believe that the physical disorder in mice indicates a defect in motor neurons."

　　Conversely, mice lacking Miro1 in the brain and spinal cord are fine at birth, but quickly develop signs of neurological problems, such as a raised spine, difficulty moving, and clenched feet, and die about 35 days after birth . According to Shaw, these symptoms are similar to motor neuron diseases.

　　She said: "The function of mitochondria in the cells seems to be good, and the level of calcium is normal. This is the first time that restricting the movement and distribution of mitochondria may lead to neurological diseases."

　　The co-author of this article, Dr. Stefan M. Pulst from the Department of Neurology at the University of Utah, said that the process of mitochondrial transport is very important, not only for motor neurons, but also for other neurons. "The Miro1 protein and two animal models represent a breakthrough in the study of ALS (gradual freezing) and other neurodegenerative diseases."

　　Although more research is needed, this research opens up the possibility of developing a new drug that partially corrects mitochondrial distribution defects to slow the progression of motor neuron disease. First, Shaw wanted to create a model to knock out the Miro1 gene in adult mice to see if the results could mimic neurological diseases.