In most cases of amyotrophic lateral¹ sclerosis (ALS肌萎缩侧索硬化症), or Lou Gehrig's disease, a toxin² released by cells that normally nurture³ neurons in the brain and spinal⁴ cord can trigger loss of the nerve cells affected⁵ in the disease, Columbia researchers reported today in the online edition of the journal Neuron. The toxin is produced by star-shaped cells called astrocytes（星形胶质细胞） and kills nearby motor neurons. In ALS, the death of motor neurons causes a loss of control over muscles required for movement, breathing, and swallowing. Paralysis⁶ and death usually occur within 3 years of the appearance of first symptoms.

 

The report follows the researchers' previous study, which found similar results in mice with a rare, genetic⁷ form of the disease, as well as in a separate study from another group that used astrocytes derived⁸ from patient neural⁹ progenitor¹⁰ cells. The current study shows that the toxins¹¹ are also present in astrocytes taken directly from ALS patients.

 

"I think this is probably the best evidence we can get that what we see in mouse models of the disease is also happening in human patients," said the study's senior author, Serge Przedborski, MD, PhD, the Page and William Black Professor of Neurology (in Pathology and Cell Biology), Vice¹² Chair for Research in the Department of Neurology, and co-director of Columbia's Motor Neuron Center.

 

The findings also are significant because they apply to the most common form of ALS, which affects about 90 percent of patients. Scientists do not know why ALS develops in these patients; the other 10 percent of patients carry one of 27 genes¹³ known to cause the disease.

 

"Now that we know that the toxin is common to most patients, it gives us an impetus¹⁴ to track down this factor and learn how it kills the motor neurons," Dr. Przedborski said. "Its identification has the potential to reveal new ways to slow down or stop the destruction of the motor neurons."

 

In the study, Dr. Przedborski and study co-authors Diane Re, PhD, and Virginia Le Verche, PhD, associate research scientists, removed astrocytes from the brain and spinal cords of six ALS patients shortly after death and placed the cells in petri dishes next to healthy motor neurons. Because motor neurons cannot be removed from human subjects, they had been generated from human embryonic¹⁵ stem cells in the Project A.L.S./Jenifer Estess Laboratory for Stem Cell Research, also at CUMC.

 

Within two weeks, many of the motor neurons had shrunk and their cell membranes¹⁶ had disintegrated¹⁷; about half of the motor neurons in the dish had died. Astrocytes removed from people who died from causes other than ALS had no effect on the motor neurons. Nor did other types of cells taken from ALS patients.

 

The researchers confirmed that the cause of the motor neurons' death was a toxin released into the environment by immersing healthy motor neurons in the astrocytes' culture media. The presence of the media, even without astrocytes, killed the motor neurons.

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