Enzyme mutation linked to inherited neurodegenerative disease in kids and teens

April 25 (ANI): A new study has identified mutations in an enzyme that may contribute to possible therapy target for Friedreich’s ataxia.

Friedreich’s ataxia is an inherited neurodegenerative disease of children and teens which is associated with the deficiency of frataxin, a protein that balances iron in mitochondria, which are the structures that convert nutrients into energy for cells. The primary symptoms of the disease include 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.

The study was conducted by a team of researcher led by Grazia Isaya at the Mayo Clinic.

As part of the study, researchers examined the enzyme which is responsible for breaking down 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,” Isaya said.

Researchers found 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.

“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.

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,” Isaya said.

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.

“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,” Isaya said.

The findings of the research were published in the April issue of the Proceedings of the National Academy of Sciences (PNAS). (ANI)