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\n<\/div>\n Audhya explains that many scientists haven\u2019t researched spastic paraplegias because there hasn\u2019t been a good model to study the disease\u2019s origins or test therapeutics. Previous mouse models haven\u2019t worked because the neuronal pathways that carry movement-related information throughout the body appear to be too different from those in humans, and researchers have not yet pursued human clinical trials.<\/p>\n Audhya worked with an interdisciplinary team of UW\u2013Madison researchers to study a specific mutation that causes HSP in young children. They then used what they learned to create a better model \u2014 in rats.<\/p>\n The mutation the researchers chose works on a protein called Trk-fused gene, or TFG. Healthy TFG proteins work inside nerve cells, or neurons, to carry other proteins from one part of the cell to another. A neuron\u2019s job is to carry messages in the form of electrical signals between the brain and rest of the body.<\/p>\n The proteins that depend on TFG for their transport keep these neuronal pathways healthy, helping to manage which electric signals the brain sends to the body and which signals to inhibit. By balancing the right levels of stimulation, neurons can direct movements like contract the leg muscles involved in walking.<\/p>\n In young children with a mutation on their TFG gene, neuronal proteins don\u2019t move through their nerve cells efficiently. Audhya says this may create an imbalance of electrical stimulation that allows an abundance of electrical signals to be sent to the lower extremities, resulting in elevated muscle tone. Over time, the excessive muscle tone leads to a loss of motor function.<\/p>\n \u201cYou can imagine if you extend your leg really hard, and you put all your energy into flexing that muscle, it\u2019s really hard to move it,\u201d says Audhya, who is also the senior associate dean for basic research, biotechnology and graduate studies in the UW School of Medicine and Public Health.<\/p>\n Searching for a workable model, the researchers turned to rats to help these children. The team used CRISPR gene editing technology to create in rat embryos the mutations that lead to HSP. This allowed them to study how the disease progresses from early development and monitor the progression of symptoms after birth.<\/p>\n Not only are the rats\u2019 neuronal pathways closer to humans\u2019, but the researchers saw that symptoms developed similarly in rats to those seen in children with HSP. It also happened on a fast enough timescale that scientists should be able to easily test the viability of potential therapeutics.<\/p>\n \u201cExercise has been the only therapy that exists for these patients, and that\u2019s really unsatisfactory,\u201d Audhya says. \u201cI think we\u2019ve made a major leap forward in just having a model where you can test out different hypotheses. That\u2019s big, from my perspective.\u201d<\/p>\n The intricate details involved in biomolecular chemistry may seem mundane to some, but basic science like this fascinates Audhya. It wasn\u2019t until he received a grant from the\u00a0Spastic Paraplegia Foundation<\/a>, which put him in contact with patients who have HSP, that he fully understood the potential impact his work could have.<\/p>\n \u201cThese are populations that are underserved. A pharma company is not likely to spend huge resources for an affected population that\u2019s so small. Instead, they\u2019re going to focus on diseases like Alzheimer\u2019s and Parkinson\u2019s,\u201d he says. \u201cSo, I felt here\u2019s a disease that is broadly overlooked, underinvested in, and here\u2019s an area where we can make an impact.\u201d<\/p>\n Audhya said he hopes this new model, which was published in the Proceedings of the National Academy of Sciences, will inspire more scientists to study HSPs to improve the understanding of the disease\u2019s development and to eventually improve access to therapeutics that will help children living with it.<\/p>\n![\"Image](\"https:\/\/www.wisconsin.edu\/all-in-wisconsin-new\/wp-content\/uploads\/sites\/378\/2022\/10\/MAD_research-medical_HSPTFGNeuron_feature-scaled.jpg\")
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