Scientists shed new light on cause of inherited movement disorder

Jul 22, 2009

University of Utah School of Medicine researchers and their colleagues at University of Texas (UT) Southwestern Medical Center have found strong evidence that abnormal calcium signaling in neurons may play an important role in the development of spinocerebellar ataxia type 2 (SCA2), a disorder causing progressive loss of coordination, speech difficulty, and abnormal eye movements. Their findings are published in the July 27, 2009 issue of Journal of Neuroscience.

SCA2 is an inherited neurodegenerative disease that predominantly affects neurons called Purkinje cells in the cerebellum, the region of the brain that controls voluntary muscle movements, balance, and posture. It is one of a group of genetic disorders characterized by ataxia, or loss of muscle coordination.

"We have known for some time that, at a molecular level, SCA2 is caused by glutamine repeat mutations in the ataxin-2 gene, but the exact mechanism of Purkinje cell degeneration is not well understood," says Stefan-M. Pulst, MD, University of Utah professor and chair of neurology, member of the Brain Institute at the University of Utah, and contributor author on this study. Pulst's group also discovered the ataxin-2 gene in 1996.

The glutamine repeat mutations found in SCA2 are also found in other neurodegenerative diseases, including Huntington disease (HD) and spinocerebellar ataxia type 3 (SCA3). It is commonly assumed that these disorders share a common pathogenic mechanism. Ilya Bezprozvanny, PhD, associate professor of physiology at UT Southwestern Medical Center, and his group had previously uncovered evidence that deranged calcium signaling played an important role in the pathology of HD and SCA3, so they thought that abnormal calcium signaling might also be involved in SCA2.

Calcium signaling refers to the movement or release of as a form of cellular communication. Bezprozvanny and his colleagues demonstrated that the mutant ataxin-2 gene strongly associated with an intracellular calcium release channel, increasing the sensitivity of the channel to activation. They also found that enhanced calcium signaling contributed to the death of Purkinje cells in cell culture, but this effect could be attenuated by dantrolene, a stabilizer of intracellular calcium signaling. Bezprozvanny and his colleagues then approached Pulst, who had developed a mouse model of SCA2, in order to test whether these results could be replicated in genetically modified mice.

The authors discovered that dantrolene was effective in alleviating motor coordination deficits in mice with a mutant ataxin-2 gene. After being fed dantrolene for a period of nine months, these mice were found to have motor coordination that was similar to normal mice and they did not suffer any significant adverse effects from long-term treatment with the calcium signaling stabilizer. The scientists also discovered that, beyond the positive effects on coordination, feeding dantrolene to mice with a mutant ataxin-2 gene reduced the death of Purkinje cells in the cerebellum.

"We were all elated to find that dantrolene had a pronounced effect in our mice," says Pulst. "It prevented deterioration in motor function and Purkinje cell death. "

Dantrolene is approved for use in humans for the treatment of muscle spasticity. "Although it showed effects in mice with ataxia, it could have major side effects in human patients with ataxia because it may cause sedation and muscle weakness. Therefore, this drug should be evaluated in controlled clinical trials before wide-spread use in SCA2 patients," cautions Pulst.

Taken together with their previous studies on HD and SCA3, the research group now has evidence that deranged calcium signaling contributes to the pathogenesis of at least three inherited ataxias. This strongly suggests that abnormal neuronal calcium signaling may also be involved in other neurodegenerative diseases caused by glutamine repeat mutations.

It is estimated that SCA2 affects as many as one or two in every 100,000 people. " like HD and SCA2 are progressive and have no known cures at this moment," according to Pulst. "Calcium signaling stabilizers such as dantrolene or similar compounds may provide a new avenue for investigation in the laboratory and in clinical trials to limit disability and disease progression."

Source: University of Utah Health Sciences (news : web)

Explore further: Know the brain, and its axons, by the clothes they wear

add to favorites email to friend print save as pdf

Related Stories

Study suggests a second dimension to Alzheimer's disease

Sep 07, 2006

The genes responsible for an inherited form of Alzheimer's disease play a direct role within cells that has largely been overlooked, according to a report in the September 8, 2006 issue of the journal Cell, published by Cel ...

Mechanism explains calcium abnormalities in Alzheimer's brain

Jun 25, 2008

A new study uncovers a mechanism that directly links mutations that cause early onset Alzheimer's disease (AD) with aberrant calcium signaling. The research, published by Cell Press in the June 26th issue of the journal Neuron, provid ...

Calcium may be the key to understanding Alzheimer's disease

Jul 18, 2008

Researchers at the University of Pennsylvania School of Medicine have shown that mutations in two proteins associated with familial Alzheimer's disease disrupt the flow of calcium ions within neurons. The two proteins, called ...

Researchers identify missing target for calcium signaling

Apr 22, 2009

An international study led by Ohio State University neuroscience researchers describes one of the missing triggers that controls calcium inside cells, a process important for muscle contraction, nerve-cell transmission, insulin ...

Recommended for you

Know the brain, and its axons, by the clothes they wear

Apr 18, 2014

(Medical Xpress)—It is widely know that the grey matter of the brain is grey because it is dense with cell bodies and capillaries. The white matter is almost entirely composed of lipid-based myelin, but ...

Turning off depression in the brain

Apr 17, 2014

Scientists have traced vulnerability to depression-like behaviors in mice to out-of-balance electrical activity inside neurons of the brain's reward circuit and experimentally reversed it – but there's ...

Rapid whole-brain imaging with single cell resolution

Apr 17, 2014

A major challenge of systems biology is understanding how phenomena at the cellular scale correlate with activity at the organism level. A concerted effort has been made especially in the brain, as scientists are aiming to ...

User comments : 0

More news stories

Filipino tests negative for Middle East virus

A Filipino nurse who tested positive for the Middle East virus has been found free of infection in a subsequent examination after he returned home, Philippine health officials said Saturday.

Study says we're over the hill at 24

(Medical Xpress)—It's a hard pill to swallow, but if you're over 24 years of age you've already reached your peak in terms of your cognitive motor performance, according to a new Simon Fraser University study.

NASA's space station Robonaut finally getting legs

Robonaut, the first out-of-this-world humanoid, is finally getting its space legs. For three years, Robonaut has had to manage from the waist up. This new pair of legs means the experimental robot—now stuck ...

Ex-Apple chief plans mobile phone for India

Former Apple chief executive John Sculley, whose marketing skills helped bring the personal computer to desktops worldwide, says he plans to launch a mobile phone in India to exploit its still largely untapped ...

Egypt archaeologists find ancient writer's tomb

Egypt's minister of antiquities says a team of Spanish archaeologists has discovered two tombs in the southern part of the country, one of them belonging to a writer and containing a trove of artifacts including reed pens ...

Airbnb rental site raises $450 mn

Online lodging listings website Airbnb inked a $450 million funding deal with investors led by TPG, a source close to the matter said Friday.