Scientists in Australia Create Worm Model for CMT Gene Research

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Scientists have developed a new animal model of X-linked Charcot-Marie-Tooth disease type 6, or CMTX6, which is caused by a mutation in the gene PDK3.

This new worm model — the first for CMTX6 in a living organism, according to researchers — may provide insights into treatment approaches for different forms of CMT and other related conditions, the team said.

“Despite the advancement in our understanding of genetic causes of CMT, it is still not clear how these genetic mutations lead to cell specific (neuronal) and spatial-specific (peripheral) degeneration in patients. Consequently, there is still no specific treatment or cure available for CMT,” the researchers wrote.

“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,” they wrote.

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Titled “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,” the study was published in the journal Human Molecular Genetics.

Mutations in more than 90 different genes have been shown to cause CMT. While these different genetic mutations cause similar disease symptoms, the exact biological consequences of individual CMT-causing mutations remain largely obscure. In order to understand the impact of disease-causing mutations, it’s helpful for researchers to have an animal model of the disease. 

“Animal models that recapitulate pathogenic [disease-causing] in vivo [in the body] events in patients are crucial for investigating mechanisms of axonal degeneration and developing therapies for CMT,” the researchers wrote.

To that end, scientists in Australia created a CMT animal model using — a type of nematode, or roundworm, also known as an eelworm, which is commonly used in biological research — with the aim of gaining insight into the biological effects of a mutation in the PDK3 gene called p.R158H.

This mutation has been reported to cause CMTX6 in unrelated families in Australia and Korea; the researchers had previously studied the mutation’s effect in cell models. Notably, X-linked means the affected gene is located on the X chromosome.

The scientists used genetic engineering to insert the mutated gene into the nematodes’ genomes, or genetic code. While some of the worms were engineered to have the altered gene in every cell in their body, others were engineered to only have it in GABAergic motor neurons. These nerve cells communicate using a signaling molecule called GABA and play a major role in controlling the worms’ movements.

A battery of biological assessments was then performed to characterize the mutant worms.

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The results showed that worms harboring the mutation had reduced body width, and also had abnormalities in synapses — the connections between neurons — characteristic of CMT. The worms’ cells showed impairments in energy metabolism, as well as an increased susceptibility to a kind of cell damage called oxidative stress, which is caused by highly reactive oxygen-containing molecules. When produced specifically in GABAergic neurons (along with the excessive activity of the healthy human gene), the disease-causing mutation also led to the death of nerve cells in the worms and caused abnormalities in movement.

“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,” the researchers wrote.

They added that the new animal model “compliments our previously established CMTX6 cellular models and will serve as an in vivo [in living animals] platform for screening drugs that might help stop the disease progression.”

“Given that [cellular] energy deficits are associated with other forms of CMT and various other neurodegenerative diseases, pharmacological intervention studies to reverse energy deficits in our CMTX6 model may have a significant impact on the study of neurodegenerative disorders,” the team concluded.