Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders caused by genetic mutations. They increase muscle tone in the lower extremities of tens of thousands of children, causing leg weakness and ultimately affecting their ability to crawl and walk.

“A six-month-old child with these mutations begins to show signs of the disease,” says Anjon Audhya, a professor in UW-Madison’s Department of Biomolecular Chemistry. “Between the ages of two and her five, these children are wheelchair bound and unfortunately unable to walk.”

Audhya explains that not many scientists have studied spastic paraplegia. This is because there were no suitable models to study the origins of this disease or to test treatments. Previous mouse models haven’t worked because the neural pathways that carry movement-related information throughout the body appear to be too different from those in humans, and researchers are still conducting human clinical trials. not.

Audhya collaborated with a multidisciplinary team of researchers at UW-Madison to study specific mutations that cause HSPs in young children. Then I used what I learned to build a better model – in rats.

The researchers’ chosen mutation works in a protein called the Trk fusion gene (TFG). A healthy TFG protein works within a nerve cell or neuron to carry other proteins from one part of the cell to another. The job of neurons is to carry messages in the form of electrical signals between the brain and other parts of the body.

Proteins that rely on TFG for transport help keep these neural pathways healthy and help manage the electrical and inhibitory signals the brain sends to the body. , neurons can direct movements such as contracting the leg muscles involved in walking.

In infants with mutations in the TFG gene, neuronal proteins cannot efficiently migrate through neurons. Audhya says this can cause an imbalance in electrical stimulation, resulting in more electrical signals being sent to the lower extremities, resulting in increased muscle tone. Over time, excessive muscle tension leads to loss of motor function.

“You can imagine stretching your leg very strongly and putting all your effort into flexing that muscle. It’s very difficult to move,” UW School of Medicine and Public Health.

In search of a viable model, the researchers turned to rats to help these children.The team used CRISPR gene-editing technology to create mutations in rat embryos that lead to HSPs. . This allowed them to study how the disease progressed from early development and monitor the progression of symptoms after birth.

Not only are rat neuronal pathways more closely related to humans, but researchers have also found that rats develop symptoms similar to those seen in HSP children. It also occurred on a fast enough timescale to allow scientists to easily test the viability of potential treatments.

“Exercise is the only treatment that exists for these patients, and it’s not really satisfactory,” says Audhya. I think we’ve made a big leap, and from my perspective, that’s a big thing.”

The intricate details involved in biomolecular chemistry may seem mundane to some, but basic science like this fascinates Audhya. After receiving a grant from the Spastic Paraplegia Foundation and coming into contact with HSP patients, he fully understood the impact his work could have.

“These are underserved populations. Pharmaceutical companies are unlikely to spend enormous resources on very few affected populations. “We would focus on disease,” he says. “

Audhya said the new model will encourage more scientists to study HSPs, gain a better understanding of how the disease progresses, and ultimately improve access to treatments that help children living with HSPs. said he wanted to

This work was supported by grants from the National Institutes of Health (R35GM134865, R01NS124165, R21NS120386)..