Charcot–Marie–Tooth disease (CMT) is one of the hereditary motor and sensory neuropathies, a group of varied inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. Currently incurable, this disease is the most commonly inherited neurological disorder, affecting nearly 3 million people worldwide.
Most people with Charcot-Marie-Tooth disease begin to see symptoms between ages 10 and 20. Patients with the condition have an average lifespan but slowly lose motor control, especially of the legs. Onset of symptoms before age 10 is associated with more severe disease, and such patients eventually may require crutches or a wheelchair.
The scientists at Washington University School of Medicine in St. Louis and Stanford University report that they have designed small compounds that have the potential to correct the mitochondrial dysfunction that leads to Charcot-Marie-Tooth and other conditions involving mitochondria. The team designed the compounds after its work in mouse cells revealed a new understanding of the 3-D structure of a key protein that is disabled in the mitochondria of patients with the disease.
The mitochondrial protein the researchers studied is called mitofusin 2. There’s a lot of interest in this protein because scientists think it also may have roles in many diseases, including diabetes and heart disease, that generally aren’t considered disorders of mitochondria. Mitofusin 2 governs whether two mitochondria are able to tether to each other and then fuse, exchanging genetic information, which is thought to be important for maintaining healthy mitochondria and, by extension, healthy tissues.
The researchers were able to design small peptides that interact with the protein and drive it toward either an active or inactive state.
One of the small molecules, dubbed GoFuse, forces mitofusin 2 into its active, healthy state, which encourages tethering and the resulting mitochondrial fusion. Conversely, the other small molecule, called TetherX, forces mitofusin 2 into its inactive state, which suppresses tethering and prevents fusion.
The hope is that GoFuse, or a similar molecule, could encourage the mitochondrial tethering and fusion that is missing in Charcot-Marie-Tooth disease. If such tethering could be restored, it could prevent or delay the loss of motor neurons that gradually paralyzes many patients with this genetic disorder.