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News from Medical News Today Apr. 28,
2007
Possible Therapy Target For
Friedreich's Ataxia
Main Category: Pediatrics / Children's Health News
Article Date: 28 Apr 2007 - 21:00 PDT
Friedreich's ataxia is one of those diseases few have heard of
unless you know someone with the condition. For that individual --
usually a child or teenager -- it is devastating. Symptoms are mild
at first: muscle weakness in the arms and legs, vision impairment
and slurred speech, but eventually the symptoms progress and most
patients become wheelchair-bound and succumb to heart failure later
in life. There is no cure at this time, but Mayo Clinic researchers
have identified mutations in an enzyme that may contribute to the
disease.
"Children and teens want to be on top of the world and having a
disease like this is devastating for them and their families in so
many different respects," says Grazia Isaya, M.D., Ph.D., senior
author of the study and a basic scientist at Mayo Clinic who
specializes in Friedreich's ataxia. "Their cognitive functions are
not impaired so they understand exactly what is happening to them."
Friedreich's ataxia is an inherited neurodegenerative disease of
children and teens and is considered an orphan disease by the
National Institutes of Health because of its rarity -- affecting one
in 40,000. It is associated with a deficiency of frataxin, a protein
that balances iron in mitochondria, which are the structures that
convert nutrients into energy for cells. A new Mayo Clinic study
published in the April issue of the Proceedings of the National
Academy of Sciences (PNAS) shows that mutations in a moonlighting
enzyme, dihydrolipoamide dehydrogenase (DLD), are responsible for
decreasing the enzyme's primary role as a metabolizer, while
increasing its role in breaking down frataxin, its second job.
Moonlighting proteins and enzymes are molecules that perform two or
more different functions. These proteins are thought to have evolved
because they can provide cells with significant advantages, namely,
the ability to increase the spectrum of metabolic activities without
increasing the number of protein-coding genes, and the ability to
coordinate different metabolic pathways.
Mutations in DLD have been linked to severe metabolic disorders in
humans, but it wasn't known that DLD was a moonlighting enzyme with
two jobs: regulating metabolism and breaking down proteins.
The PNAS study describes how Mayo investigators identified DLD's
role in reducing the amount of frataxin that is produced.
"These findings reveal a previously unrecognized mechanism by which
certain DLD mutations can simultaneously induce the loss of a
primary metabolic activity and the gain of a moonlighting
proteolytic (breaking down enzymes) activity. The latter could
contribute to the metabolic derangement associated with DLD
deficiency and represent a target for therapies of this condition,"
the authors write.
Like all proteins, frataxin is continuously synthesized, and it
carries out its function before it breaks down. Some proteins
degrade more rapidly than others, but frataxin degrades at a much
more rapid pace than other proteins. "We observed this degradation
years ago and in doing so, we decided to go after the enzyme
responsible for the degradation thinking it probably might play an
important role in the regulation of frataxin and could represent a
target therapy for Friedreich's ataxia," says Dr. Isaya.
The severity of Friedreich's ataxia is proportional to the decrease
in the levels of frataxin: the lower the frataxin, the more severe
the disease. "Yet, this correlation does not completely explain the
clinical variability because even within the same family we may see
individuals with different phenotypes -- one more severe than the
other," Dr. Isaya says.
In Friedreich's ataxia, clinicians have long hypothesized the
existence of gene modifiers -- genes that can influence the outcome
of other gene mutations. "We believe that the enzyme we've
identified is most likely a modifier of Friedreich's ataxia because
mutations in that gene could increase or decrease the levels of
frataxin in patients," she says.
Identifying and confirming the role of this moonlighting enzyme
could aid in the development of new therapies for patients with
Friedreich's ataxia. In addition, further study could confirm the
presence of mutations in the enzyme that could explain, in part,
differing clinical phenotypes among patients.
Dr. Isaya says: "Understanding protein function is central to being
able to provide individualized clinical care to patients who may,
for example, carry different mutations of this enzyme and express
different clinical phenotypes."
###
Other authors of this study include: Ngolela Esther Babady, a Ph.D.
student at Mayo Graduate School; Yuan-Ping Pang, Ph.D., director of
Mayo Clinic's Computer-Aided Molecular Design Laboratory; and Orly
Elpeleg of Hadassah Hebrew University Medical Center in Jerusalem.
The study was funded with grants from the Muscular Dystrophy
Association, American Heart Association, U.S. Department of Defense
and the National Science Foundation.
Contact: Amy Reyes
Mayo Clinic
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