Mice with a disorder resembling the type 1B form of Charcot-Marie-Tooth disease (CMT) benefited from treatment with either of two forms of oral curcumin, a component of the spice turmeric, according to researchers supported in part by MDA.
Treatment with curcumin appeared to reduce the effect of a cellular defense mechanism — the unfolded protein response — which can lead to cell death. Curcumin-treated mice had better muscle function and more normal-appearing nerve fibers than untreated mice.
The newly published mouse results, which build on preliminary findings announced in April 2010, could lead to testing of curcumin derivatives in people with the type 1B form of CMT, and possibly in those with other types of CMT. Researchers cautioned that it’s very uncertain how many other CMT-causing mutations (there are hundreds) will respond to treatment with curcumin; however, promising results have been seen in mice with a mutation that causes CMT1E.
MDA provided funding to Michael Shy, a professor of neurology at the University of Iowa Carver College of Medicine, and co-director of the MDA neuromuscular disease clinic at the University of Iowa Hospitals & Clinics in Iowa City. (Shy was at Wayne State University in Detroit until early 2012, and much of this research was conducted there.) He and his colleagues published their findings in the December 2012 issue of the journal Brain.
CMT1B results from any of a number of different mutations in the gene for the myelin protein zero (MPZ) protein.
MPZ is one of many proteins and fatlike substances found in myelin, an insulating sheath that surrounds nerve fibers and speeds the transmission of nerve signals, such as those that go from nerve cells to muscle cells.
When MPZ is malformed or deficient, the myelin sheath isn’t as effective as it needs to be for optimal nerve signal transmission. Mice and humans with MPZ mutations have sensory and motor abnormalities, particularly in the lower legs and forearms.
The mice in these experiments had a mutation in one of their two MPZ genes. The mutation is one that can cause human CMT1B, but is not the only mutation that can do so.
Shy said that, while the experiments described in the December paper were conducted in mice with one specific MPZ gene mutation, curcumin also may be useful with other mutations.
“Our results suggest that several MPZ mutations may respond to curcumin derivatives,” Shy said. “While it is true that the mutation in our mice is just one of the known CMT1B mutations, we already know that there are several others that have similar effects on cells and therefore may respond to a similar therapeutic approach.”
Compared to untreated animals, mice with a disorder mimicking human CMT1B that were treated with curcumin in sesame oil or with phosphatidylcholine curcmin:
A cellular defense mechanism known as the unfolded protein response, or UPR was reduced in the curcumin-treated mice. The UPR can protect cells from abnormally formed proteins but also can, in some situations, cause these cells to die.
The investigators speculate that reducing the effects of the UPR may protect cells and account for the beneficial effects of curcumin.
In an accompanying editorial in the same issue of Brain, author Rhys Roberts cautions that not all CMT mutations, and perhaps not even all CMT1B-causing mutations, lead to accumulations of misfolded proteins or to activation of the UPR, and that therefore the curcumin response may apply only to a small portion of the CMT population.
Roberts, a neuroscientist at the Cambridge Institute for Medical Research in the United Kingdom, notes that the mutation that affects the mice used in these experiments — known as the R98C mutation — is only one of more than 120 different CMT1B-associated mutations in the MPZ gene. He says it’s crucial to understand the effects of each mutation and to develop therapies based on these effects.
In separate communications, Shy said he agrees with Roberts but that he and his colleagues have examined the effects of nine CMT1B-causing mutations so far and have found that five of them activate the unfolded protein response, indicating that they might respond favorably to curcumin treatment.
In addition, he noted, a mutation that causes CMT1E— a different form of CMT, caused by a mutation in the PMP22 gene — falls into this category, and mice with this mutation also have been found to respond positively to oral curcumin.
“Our results suggest that MPZ mutations and possibly other mutations that activate the unfolded protein response may respond to therapies that reduce this activation,” Shy added.
“While it is true that the MPZ mutation contained in our mice reflects just one CMT1B mutation, we already know that there are at least several other CMT mutations in which the unfolded protein response is activated.
"We are currently working to determine how many of the other MPZ mutations activate this potentially harmful defense mechanism and whether these mutations or similar mutations in other forms of CMT may respond to a similar therapeutic approach."