Drug compound may help against Charcot-Marie-Tooth disease
From the WashU Newsroom…
Scientists have developed a new drug compound that shows promise as a future treatment for Charcot-Marie-Tooth disease, an inherited, often painful neurodegenerative condition that affects nerves in the hands, arms, feet and legs. The researchers used the compound to treat the nerves of mice harboring the genetic defects that cause the disease.
The new study, from Washington University School of Medicine in St. Louis, challenges some conventional wisdom regarding how patients with this disease lose the ability to move their limbs.
The study appears April 20 in the journal Science.
Charcot-Marie-Tooth is the most common inherited degenerative disease of peripheral nerves. The disease affects about one in 2,500 individuals worldwide, and there are no treatments for it. The researchers studied a form of the condition called Charcot-Marie-Tooth disease type 2A, which is caused by specific genetic mutations.
These patients have inherited mutations that affect mitochondria, the energy factories of cells. Healthy mitochondria fuse together and exchange mitochondrial DNA. This healthy mitochondrial “sex” is impaired in this disease because of mutations in a protein called mitofusin2, which governs mitochondrial fusion.
Because they can’t fuse, the mitochondria of people with this disease appear small, granular and clumped when viewed under a microscope. Until now, the small size was thought to be the main problem in the disorder. Small energy factories can’t produce enough fuel to keep nerves alive, so the cells slowly die off, the thinking went. But senior author Gerald W. Dorn II, MD, the Philip and Sima K. Needleman Professor of Medicine, suspected something else was going on.
Dorn knew the genetic mutations in this disease aren’t confined to nerves; rather, they are present in all of the mitochondria in every cell of the body. Nerve cells and, for example, heart muscle cells burn energy at high rates and need healthy, robust mitochondria for fuel. A cardiologist by training, Dorn wondered why patients with the disease don’t have heart problems.
“This disease starts with nerve loss in the feet, moves up the legs, then to the arms, but it doesn’t have major effects elsewhere,” said Dorn, also director of the School of Medicine’s Center for Pharmacogenomics. “People with Charcot-Marie-Tooth eventually may need wheelchairs, but they have normal lifespans.
“We found that the problem isn’t mitochondria that are too small, but mitochondria that can’t travel distances. In heart cells, mitochondria are packed like sardines and don’t need to move much, so there’s no problem with energy supply,” he said. “But for mitochondria to make it down a person’s leg — following the sciatic nerve from the lumbar spine to the foot — that’s akin to a 500-mile trip. If a person can’t constantly renew mitochondria, over the years the nerves start to atrophy. Once the nerves die, the muscles atrophy as well.”