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Gene Mutation Found as Possible Cause of HSP Disorders

Madison, Wisconsin - University of Wisconsin-Madison scientists may have discovered a new genetic root of hereditary spastic paraplegias, or HSPs.

 

These inherited gait disorders are part of a diverse group of neurodegenerative ailments commonly characterized by spastic weakness and eventual paralysis in the legs as a result of nerve dysfunction.

 

An assistant professor of biomolecular chemistry in the UW School of Medicine and Public Health, Dr. Anjon Audhya recently identified a plausible genetic mutation responsible for HSPs. Leveraging previous research into a protein called TFG — which controls the movement, or secretion, of growth factors and other proteins out of cells in both worms and humans — Audhya is pointing a finger at the specific mutation that affects the secretion pathway and leads to motor neuron erosion.

 

Normal TFG function supports the assembly of transport packages known as vesicles. Within cells, these vesicles move proteins and other cargo released. TFG acts specifically within the endoplasmic reticulum (ER), which is where all secreted proteins are synthesized, carbohydrates and lipids are metabolized, and some drugs and byproducts of ER function are detoxified.

 

Wisconsin scientists have identified a specific mutation in patients with HSP that disrupts normal TFG proteins from participating in vesicle transport. According to Audhya, this may cause ER damage and impede protein secretion. Because proteins play such large and complex roles in the body, this disruption of ER function is critical. Such a disruption can potentially lead to degeneration of nerve cell axons — the long fibers that transmit electrical impulses from one cell to the other — and ultimately impair communication from the brain.

 

But now that this protein mutation associated with HSPs has been identified, movement forward on the mutation’s full impact is already underway.

 

“Our goal is to recapitulate the disease in cultured cells,” said Audhya. “We plan to engineer the disease-causing mutation in TFG into neuronal cell lines and then see what the specific impact of this point mutation really is.”

 

A number of collaborators are already working with Audhya, including the UW-Madison Waisman Center, which focuses on human development, developmental disabilities, and neurodegenerative diseases like HSP disorders.

 

“There are 40 to 50 genes implicated in the disease, but in future study, we hope to find a commonality in the phenotype that we can address,” said Audhya. “Disease cure is the ultimate goal for everyone here.”

 

Audhya’s study on TFG function and its relation to HSPs, “Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum function,” is published in the Proceedings of the National Academy of Sciences.

 

The research was highly collaborative, combining human genetic studies conducted in Germany and India with biochemical and cell biological approaches performed by multiple groups at UW-Madison.



Date Published: 03/19/2013


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Last updated: 03/20/2013
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