Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.
If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.
This week’s study is…
Charcot–Marie–tooth disease causing mutation (p.R158H) in pyruvate dehydrogenase kinase 3 (PDK3) affects synaptic transmission, ATP production and causes neurodegeneration in a CMTX6 C. elegans model
We previously published about this research in a story titled “Researchers Create Worm Model to Expand CMTX6 Research” which can be found here. The study was originally published in the scientific research journal Human Molecular Genetics. You can view the full text of the study here.
What Happened?
In this study, a team of researchers have successfully developed an animal model of X-linked Charcot-Marie-Tooth disease type 6 (CMTX6). Animal models are often used to help scientists when conducting research on a certain disease or medicine. In many cases, mouse models are employed as mice share a broad biological similarity with humans and can be bred quickly and reliably in a domestic setting. However, other animals, such as dogs, pigs, or fish, can be used.
In this case, the researchers opted to develop a model using a worm, the species Caenorhabditis elegans. Though less biologically similar to humans than mice, this species has become popular for use in research involving nervous system development, as it is one of the ‘simplest’ living creatures with a nervous system. In the wild, they are only about 1 mm long and live in temperate soil environments. This variant of CMT is caused by PDK3 gene mutations, so the scientists developed the model by knocking-in the p.R158H mutation in pdhk-2, the ortholog of PDK3.
The researchers also developed models based on the overexpression of the mutant form and wild type of human PDK3 in the worms’ neurons. As the scientists anticipated, the altered C. elegans began to display differences from healthy samples. The worms showed signs of neurodegeneration that was progressive in nature as well as problems with movement. The altered worms also showed synaptic deficits consistent with CMT.
The width of the worms also became narrower. They also had energy metabolism problems and they were also more at risk of oxidative stress, a type of cell damage. The movement symptoms were reminiscent of the challenges faced by human patients with the disease.
About Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease is a hereditary disorder of the peripheral nervous system. It is most characterized by a progressive loss of touch sensation and muscle tissue in several different parts of the body. The cause of this disease is usually linked to a genetic mutation, but the mutation involved varies depending on the variant of Charcot-Marie-Tooth disease. In CMTX6, the PDK3 gene is affected. Some forms are X-linked, but others are not. Symptoms include foot drop, muscle wasting (typically in the arms, legs, and hands), painful muscle spasms, loss of sensation in the limbs, scoliosis, trouble speaking, chewing, and swallowing, and tremors. Treatment typically includes therapy and surgery in order to maintain function. There is no cure. The disease can occur early in life or as late as the 30s and 40s. To learn more about Charcot-Marie-Tooth disease, click here.
Why Does it Matter?
The successful development of an animal model for a certain disease is an achievement for research in that illness in any case. This model of C. elegans can now be used as a starting point for CMTX6 research that will provide information that studies conducted on cells in a lab cannot. The observations recorded by the scientists with their initial model have already provided new data related to cellular function and the metabolic pathways.
“The C. elegans models generated in this study recapitulate various molecular phenotypes [characteristics] observed in both the CMTX6 [cell and motor neurons models], and motor phenotypes observed in patients.”
Some of the observations that can be made with this animal model may also have valuable implications for other neurodegenerative diseases as well. The researchers were able to decisively observe problems with cellular energy metabolism, a factor that is present in many more disorders beyond CMTX6. Studies attempting to reverse this problem could be conducted on this model, with results that could provide critical insights for diseases that cause similar issues.
As a whole, animal models such as this one also serve as valuable platforms for testing potential therapies:
“These models will not only help our understanding of the cellular and biological pathways that lead to CMT but will serve as a useful platform for drug screening to identify compounds that can ameliorate disease progression or potentially cure CMT.”
The creation of the C. elegans CMTX6 model will be vital for the development of a cure for CMT.
