Adam Avery, an assistant professor of biochemistry, has been awarded a three-year, $400,000 grant to research gene mutations associated with Spinocerebellar Ataxia, a degenerative brain disorder that affects motor skills, including balance, coordination and speech.

There are at least 40 known types of Spinocerebellar Ataxia and each corresponds to a different affected gene. Avery’s research looks at Spinocerebellar Ataxia Type 5 (SCA5), which is associated with a gene that encodes for β-III-spectrin, a cytoskeletal protein responsible for maintaining the structure of Purkinje cells. These neurons are found in the cerebellum, located at the back of the brain, and control muscle coordination.

“Purkinje neurons have highly complex structures that look like the arbor of a tree. These arbors are critical for the neurons to receive and transmit signals in the brain,” Avery said. “My research is focused on the molecular mechanisms that support neuron structure and understanding how gene mutations cause breakdowns in that structure.”

As a postdoctoral fellow at the University of Minnesota, Avery conducted research on the molecular underpinnings of a gene mutation linked to SCA5. The research showed that a particular mutation in the gene encoding β-III-spectrin caused an increase in the binding of β-III-spectrin to another protein called actin. Moreover, understanding the molecular consequences of a gene mutation is critical because it lays the groundwork for the development of treatments for heritable diseases like Spinocerebellar Ataxia.

“There’s currently no cure for Spinocerebellar Ataxia,” Avery noted. “But if we can understand the disease on a molecular level, we can use that knowledge to search for molecular compounds that counteract the problem.”

Avery worked with researchers at the University of Minnesota to develop a way to screen for molecular compounds that could remedy the effects of the mutation. The screening process, which is funded by a separate NIH grant, is in progress and any compounds showing promise will be sent to Avery’s lab at OU for further characterization. The results of the screening could also complement the research being funded under Avery’s most recent NIH grant.

“Some of the mutations that we’re beginning to study under the new grant are in a region of the β-III-spectrin gene that is close to the mutation I already characterized,” Avery explained. “If those mutations have a similar molecular consequence, then the same drug could prove useful for treating them as well.”

In addition, the research could also provide insight into diseases associated with mutated genes that encode for proteins related to β-III-spectrin, including muscular dystrophy and certain forms of heart disease.

The research for Avery’s most recent NIH grant is assisted by OU doctoral student Sarah Denha, master’s student Alexandra Atang and undergraduate students Naomi Billings and Amanda Keller. As part of the grant, the researchers are also investigating the impact SCA5 mutations have on neuron structure.

“I previously developed a model in fruit flies that showed that a specific SCA5 mutation causes a set of unique defects in neuron structure,” Avery said. “Currently, we are testing if similar defects are induced by other SCA5 mutations. These studies will inform on whether distinct SCA5 mutations share a common disease pathway.”

Fruit flies are a good model for this research because they have a type of neuron that branches off like a tree arbor – similar to the human Purkinje neurons thought to be impacted by SCA5.

“The arbor part of the neuron integrates sensory information related to motor skills like walking and talking,” Avery said. “With SCA5, the arbor is much smaller than normal, which impairs neuron function and causes problems with motor activity. The more we understand about how these biochemical processes work and how various gene mutations disrupt them, the better our chances of developing therapeutics to help those impacted by the disease.”

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