Enzyme's structure reveals basis for head, reproductive organ deformities

Friday 23 August 2013

Islamabad, Aug 24 (Newswire): Scientists this month reported the molecular structural basis for severe head deformities and ambiguous reproductive organs in babies born with Antley-Bixler syndrome accompanied by an enzyme deficiency.

The team, composed of researchers from The University of Texas Health Science Center San Antonio, the Medical College of Wisconsin and Charles University in Prague, solved the atomic structure of this human enzyme with an impressive name -- NADPH-cytochrome P450 reductase, abbreviated CYPOR.

The group is the first to visualize and depict the structure of the human version of CYPOR. The scientists also reported the structure of two mutations of human CYPOR that result in congenital deformities.

"Human syndromes are caused by the deficiency of this enzyme," said Bettie Sue Masters, Ph.D., D.Sc., M.D. (Hon.), professor of biochemistry and the Robert A. Welch Foundation Distinguished Professor in Chemistry at the UT Health Science Center. "The two mutations that we characterized are responsible for severe craniofacial and steroid-production defects in humans, the latter leading to sexual ambiguities."

In the body, steroids are produced for many important functions. In CYPOR deficiency, these steroidal malfunctions are related to deformed sexual organs and other defects.

In previously published research from Dr. Masters' laboratory, addition of a riboflavin (vitamin B2) derivative reversed the defects in the mutated enzymes; this is because the vitamin makes this particular enzyme work, producing metabolites. Metabolites are the products of enzyme-generated reactions. This reversal of CYPOR defects by a riboflavin derivative is yet to be investigated in animals or humans. Foods such as liver, herbs, almonds, wheat bran, fish and cheese are rich in riboflavin.

Knowing the molecular structure of CYPOR has proved that riboflavin therapy is worth attempting, Dr. Masters said. As demonstrated by this structure, CYPOR dysfunction in patients harboring these particular mutations may possibly be prevented by riboflavin therapy within the womb, if predicted before birth, or rescued after birth in less severe cases, the authors wrote in the Aug. 4 publication.

Antley-Bixler syndrome is a rare genetic disorder characterized by a prominent forehead, underdeveloped regions in the mid-face, protruding eyes and other abnormalities. Dr. Masters and her colleagues are studying the origins of these bone development defects.

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Common cause of all forms of ALS discovered

Islamabad, Aug 24 (Newswire): The underlying disease process of amyotrophic lateral sclerosis (ALS and Lou Gehrig's disease), a fatal neurodegenerative disease that paralyzes its victims, has long eluded scientists and prevented development of effective therapies.

Scientists weren't even sure all its forms actually converged into a common disease process.

But a new Northwestern Medicine study for the first time has identified a common cause of all forms of ALS.

The basis of the disorder is a broken down protein recycling system in the neurons of the spinal cord and the brain. Optimal functioning of the neurons relies on efficient recycling of the protein building blocks in the cells. In ALS, that recycling system is broken. The cell can't repair or maintain itself and becomes severely damaged.

The discovery by Northwestern University Feinberg School of Medicine researchers, published in the journal Nature, provides a common target for drug therapy and shows that all types of ALS are, indeed, tributaries, pouring into a common river of cellular incompetence.

"This opens up a whole new field for finding an effective treatment for ALS," said senior author Teepu Siddique, M.D., the Les Turner ALS Foundation/Herbert C. Wenske Professor of the Davee Department of Neurology and Clinical Neurosciences at Northwestern's Feinberg School and a neurologist at Northwestern Memorial Hospital. "We can now test for drugs that would regulate this protein pathway or optimize it, so it functions as it should in a normal state."

The discovery of the breakdown in protein recycling may also have a wider role in other neurodegenerative diseases, specifically the dementias. These include Alzheimer's disease and frontotemporal dementia as well as Parkinson's disease, all of which are characterized by aggregations of proteins, Siddique said. The removal of damaged or misfolded proteins is critical for optimal cell functioning, he noted.

This breakdown occurs in all three forms of ALS: hereditary, which is called familial; ALS that is not hereditary, called sporadic; and ALS that targets the brain, ALS/dementia.

In related research, Feinberg School researchers also discovered a new gene mutation present in familial ALS and ALS/dementia, linking these two forms of the disease.

Siddique has been searching for the causes and underlying mechanism of ALS for more than a quarter century. He said he was initially drawn to it because, "It was one of the most difficult problems in neurology and the most devastating, a disease without any treatment or known cause."

Siddique's efforts first showed in 1989 that molecular genetics techniques were applicable to ALS, then described the first ALS gene locus in 1991, which led to the discovery of SOD1 and engineering of the first genetic animal model for ALS.

ALS affects an estimated 350,000 people worldwide, including children and adults, with about 50 percent of people dying within three years of its onset. In the motor disease, people progressively lose muscle strength until they become paralyzed and can no longer move, speak, swallow and breathe. ALS/dementia targets the frontal and temporal lobes of the brain, affecting patients' judgment, the ability to understand language and to perform basic tasks like planning what to wear or organizing their day.

"These people in the prime of their lives and the peak of their productivity get this devastating illness that kills them," Siddique said. "The people who get ALS/dementia, an even more vicious disease, have a double whammy."

Feinberg School scientists found the cause of ALS by discovering a protein, ubiquilin2, whose critical job is to recycle damaged or misfolded proteins in motor and cortical neurons and shuttle them off to be reprocessed.

In people with ALS, Feinberg researchers found ubiquilin2 isn't doing its job. As a result, the damaged proteins and ubiquilin2 loiter and accumulate in the motor neurons in the spinal cord and cortical and hippocampal neurons in the brain. The protein accumulations resemble twisted skeins of yarn -- characteristic of ALS -- and cause the degeneration of the neurons.

Researchers found ubiquilin2 in these skein-like accumulations in the spinal cords of ALS cases and in the brains of ALS/dementia cases.

The scientists also discovered mutations in ubiquilin2 in patients with familial ALS and familial ALS/dementia. But the skein-like accumulations were present in people's brains and spinal cords in all forms of ALS and ALS/dementia, whether or not they had the gene mutation.

"This study provides robust evidence showing a defect in the protein degradation pathway causes neurodegenerative disease," said Han-Xiang Deng, M.D., lead author of the paper and associate professor of neurology at the Feinberg School. "Abnormality in protein degradation has been suspected, but there was little direct evidence before this study." The other lead author is Wenjie Chen, senior research technologist in neurology.

About 90 percent of ALS is sporadic, without any known cause, until this study. The remaining 10 percent is familial. To date, mutations in about 10 genes, several of which were discovered at Northwestern, including SOD1 and ALSIN, account for about 30 percent of classic familial ALS, noted Faisal Fecto, M.D., study co-author and a graduate student in neuroscience at Feinberg.

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New 'bionic' leg gives amputees a natural gait

Islamabad, Aug 24 (Newswire): A new lower-limb prosthetic developed at Vanderbilt University allows amputees to walk without the leg-dragging gait characteristic of conventional artificial legs.

The device uses the latest advances in computer, sensor, electric motor and battery technology to give it bionic capabilities: It is the first prosthetic with powered knee and ankle joints that operate in unison. It comes equipped with sensors that monitor its user's motion. It has microprocessors programmed to use this data to predict what the person is trying to do and operate the device in ways that facilitate these movements.

A passive leg is always a step behind me. The Vanderbilt leg is only a split-second behind.""When it's working, it's totally different from my current prosthetic," said Craig Hutto, the 23-year-old amputee who has been testing the leg for several years. "A passive leg is always a step behind me. The Vanderbilt leg is only a split-second behind."

The bionic leg is the result of a seven-year research effort at the Vanderbilt Center for Intelligent Mechatronics, directed by Michael Goldfarb, the H. Fort Flowers Professor of Mechanical Engineering.

The project was initially funded by a seed grant from the National Science Foundation, followed by a development grant from the National Institutes of Health. Key aspects of the design have been patented by the university, which has granted exclusive rights to develop the prosthesis to Freedom Innovations, a leading developer and manufacturer of lower limb prosthetic devices.

"With our latest model, we have validated our hypothesis that the right technology was available to make a lower-limb prosthetic with powered knee and ankle joints," said Goldfarb. "Our device illustrates the progress we are making at integrating man and machine."

The Vanderbilt prosthesis is designed for daily life. It makes it substantially easier for an amputee to walk, sit, stand, and go up and down stairs and ramps. Studies have shown that users equipped with the device naturally walk 25 percent faster on level surfaces than when they use passive lower-limb prosthetics. That is because it takes users 30 to 40 percent less of their own energy to operate.

"Going up and down slopes is one of the hardest things to do with a conventional leg," said Hutto. "So I have to be conscious of where I go because I can get very tired walking up and down slopes. But that won't be a problem with the powered leg because it goes up and down slopes almost like a natural leg."

Recent technological advances have allowed the Vanderbilt engineers to produce a device that weighs about nine pounds -- less than most human lower legs -- and can operate for three days of normal activity, or 13 to 14 kilometers of continuous walking, on a single charge. They have also dramatically reduced the amount of noise that the latest model makes, although it is slightly louder than they would like.

One of the latest capabilities that the engineers have added is an anti-stumble routine. If the leg senses that its user is starting to stumble, it will lift up the leg to clear any obstruction and plant the foot on the floor.

In order to incorporate all the improvements, the prosthetic's hardware design has gone through seven versions and its electronics board has been redone 15 times.

According to Goldfarb, it was tough to make the prosthetic light and quiet enough. In particular, it was difficult to fit the powerful motors and drive train that they needed into the volume available. The biggest technical challenge, however, was to develop the control system.

"As you add greater capability, you are also adding greater liability," he said. "Not only does the controller have to perform individual operations reliability, but it has to perform several operations at the same time and not get confused."

The Center for Intelligent Mechatronics is also developing an anthropomorphic prosthetic arm project and an advanced exoskeleton to aid in physical therapy.

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