An abnormality discovered by U-M researchers in mice with Spinocerebellar Ataxia type 3 could represent a target for therapy.

In a paper published this week in the Journal of Neuroscience, U-M researchers found that a particular dysfunction in neurons occurs well before the death of neurons, which is typical of this ataxia. That dysfunction, an alteration in neuronal firing, could be a target for potential treatments.

"We've established in a mouse model of disease that there is a specific defect in neuronal function, early in the disease, well before the death of neurons," said lead author Vikram G. Shakkottai, M.B.B.S., Ph.D., assistant professor in U-M's Department of Neurology.

"With further study, we hope to find that early neuronal dysfunction, preceding neuronal loss, could be relevant to understanding the motor problems in a broader range of ataxias."

About 300,000 people in the U.S. suffer from ataxias and possibly up to 20,000 have the type that was the focus of this study: Spinocerebellar Ataxia type 3, which is also known as Machado-Joseph disease, says co-author Henry Paulson, M.D., Ph.D., Lucille Groff Professor of Neurology at U-M.

Symptoms of the disease are slowly progressive clumsiness and problems in walking and maintaining balance, along with difficulty with swallowing and aspiration. It is an untreatable condition, and no medication currently is available to slow the course of the disease.

It is the most common dominantly inherited ataxia and belongs to a class of at least nine genetic disorders called polyglutamine expansion diseases. Mutations in polyglutamine diseases are abnormally long repeats of a normal repetition of three letters of the DNA genetic code.

"Ataxia is, for the most part, a mystery. Many forms of ataxia are fatal, untreatable disorders and this study provides a clue to early dysfunction in brain cells, an advance in the way we think about this class of degenerative diseases," says Paulson, who also is director of U-M's Michigan Alzheimer's Disease Center.

The study showed that activation of a specific type of potassium channel was successful in improving the motor dysfunction in the mice and could be a potential route to therapy of the human disorder.

"Our findings reinforce the idea that neuronal dysfunction resulting from problems in channels may underlie some of the motor symptoms typical of these ataxias, particularly early in the course of the disease. These early defects in neuronal function may be a target for therapies," says Shakkottai.

Additional authors: Maria do Carmo Costa and James M. Dell'Orco, both of the U-M Department of Neurology; Ananthakrishnan Sankaranarayanan, of the University of California-Davis; and Heike Wulff, University of New Orleans.

Source: University of Michigan Health System