Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Study links normal function of protein, not its build up inside cells, to death of neurons

A new study led by St. Jude Children's Research Hospital scientists signals hope for treatment of a neurodegenerative disease and a new model for understanding the mechanism at work in other more common neurodegenerative disorders

A study led by St. Jude Children's Research Hospital investigators links the muscle weakness and other symptoms of a rare neurodegenerative disease to a misstep in functioning of a normal protein, rather than its build-up inside cells. The finding offers insight into the mechanism driving common nervous system disorders like Parkinson's and Alzheimer's diseases.

The work advances understanding of how the inherited mistake at the heart of spinobulbar muscular atrophy (SBMA) leads to the death of neurons in the brain and spinal cord. Investigators showed that the underlying mutation caused an amplification of the protein's normal function. The work appears in the September 23 online edition of the scientific journal Neuron.

"The idea that toxicity is mediated by the native, or normal, function of the protein itself is a departure from conventional wisdom. This research adds to growing evidence the principle applies very broadly in other neurodegenerative disorders, including Alzheimer's and Parkinson's diseases," said J. Paul Taylor, M.D., Ph.D., an associate member in the St. Jude Department of Developmental Neurobiology and the paper's senior author.

The current neurodegenerative disease model links the disorders to a toxic build-up of improperly folded proteins inside cells. Taylor said: "Our findings suggest the focus on protein aggregation inside cells may be misplaced." Developing therapies that target the normal protein function will likely be easier and more effective, he added.

Medications are already available to block the androgen receptor (AR) protein, which is mutated in SBMA. Work is now underway in Taylor's laboratory to identify drugs that more selectively block AR functioning.

SBMA belongs to a family of eight disorders, including Huntington's disease, which stem from an overabundance of the same small, repeated sequence of DNA known as a trinucleotide. Such repetitions are common throughout the genome, but problems arise when they occur too frequently. That is what happens in the estimated 1 in 50,000 males with SBMA.

In the case of SBMA, the repeated sequence occurs in the gene for the androgen receptor. The repeated nucleotide sequence CAG is protein-production shorthand for an amino acid called glutamine. The resulting androgen receptor (AR) protein includes surplus glutamine.

After earlier work by other investigators showed that blocking testosterone prevented male mice with the SBMA mutation from developing the disease, Taylor and his colleagues set out to track what happened inside cells after the hormone bound to the mutated AR protein.

Working in a Drosophila fruit fly model of the disease, the scientists identified a small region of the AR protein, known as the AF-2 domain, which played a pivotal role.

Using a variety of techniques, researchers demonstrated they could rescue the cells by preventing certain members of a family of proteins called coregulators from binding to the AF-2 domain. Coregulators partner with AR and other transcription factors to regulate gene expression.

"In this study, we showed the ability of the mutant protein to interact with the normal binding partners is an essential step in the cascade of degeneration. By blocking it, we block degeneration," Taylor said. He added that the AF-2 domain is far from the mutated region of the AR protein. "That would be unexpected if the mechanism of toxicity were related to the protein aggregating," he explained.

Meanwhile, investigators are still studying why the protein's change in function is so deadly to cells. Taylor noted that research into inherited diseases like SBMA has historically provided important clues into the mechanisms at work in other more common neurodegenerative disorders, including Alzheimer's.

The findings also hold hope that treating or preventing SBMA by selectively disrupting AF-2 binding will soon be possible, Taylor said. "Selectively blocking the hormone will be key if we hope to prevent the side effects associated with androgen ablation in males," he said. The side effects include bone thinning, infertility or blocked sexual maturation.

The study also suggests the need to begin treatment earlier. If the damage to motor neurons begins with the hormone surge of puberty rather than the accumulation of mis-folded proteins, therapies must begin in childhood, Taylor said.

Natalia Nedelsky, of St. Jude and the University of Pennsylvania, is the study's first author. The co-authors are Maria Pennuto, Italian Institute of Technology, Genoa, Italy; Isabella Palazzolo, National Institute of Neurological Disorders and Stroke; Zhiping Nie, University of Pennsylvania; and Rebecca Smith, Jennifer Moore and Geoffrey Neale, all of St. Jude.

The study was funded in part by the Muscular Dystrophy Association, the Kennedy's Disease Association, the National Institutes of Health and ALSAC.

St. Jude Children's Research Hospital

St. Jude Children's Research Hospital is internationally recognized for its pioneering research and treatment of children with cancer and other catastrophic diseases. Ranked the No. 1 pediatric cancer hospital by Parents magazine and the No. 1 children's cancer hospital by U.S. News & World Report, St. Jude is the first and only National Cancer Institute-designated Comprehensive Cancer Center devoted solely to children. St. Jude has treated children from all 50 states and from around the world, serving as a trusted resource for physicians and researchers. St. Jude has developed research protocols that helped push overall survival rates for childhood cancer from less than 20 percent when the hospital opened to almost 80 percent today. St. Jude is the national coordinating center for the Pediatric Brain Tumor Consortium and the Childhood Cancer Survivor Study. In addition to pediatric cancer research, St. Jude is also a leader in sickle cell disease research and is a globally prominent research center for influenza.

Founded in 1962 by the late entertainer Danny Thomas, St. Jude freely shares its discoveries with scientific and medical communities around the world, publishing more research articles than any other pediatric cancer research center in the United States. St. Jude treats more than 5,700 patients each year and is the only pediatric cancer research center where families never pay for treatment not covered by insurance. St. Jude is financially supported by thousands of individual donors, organizations and corporations without which the hospital's work would not be possible. In 2010, St. Jude was ranked the most trusted charity in the nation in a public survey conducted by Harris Interactive, a highly respected international polling and research firm. For more information, go to

Summer Freeman | EurekAlert!
Further information:

More articles from Studies and Analyses:

nachricht Rutgers-led innovation could spur faster, cheaper, nano-based manufacturing
14.02.2018 | Rutgers University

nachricht New study from the University of Halle: How climate change alters plant growth
12.01.2018 | Martin-Luther-Universität Halle-Wittenberg

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Researchers at Fraunhofer monitor re-entry of Chinese space station Tiangong-1

In just a few weeks from now, the Chinese space station Tiangong-1 will re-enter the Earth's atmosphere where it will to a large extent burn up. It is possible that some debris will reach the Earth's surface. Tiangong-1 is orbiting the Earth uncontrolled at a speed of approx. 29,000 km/h.Currently the prognosis relating to the time of impact currently lies within a window of several days. The scientists at Fraunhofer FHR have already been monitoring Tiangong-1 for a number of weeks with their TIRA system, one of the most powerful space observation radars in the world, with a view to supporting the German Space Situational Awareness Center and the ESA with their re-entry forecasts.

Following the loss of radio contact with Tiangong-1 in 2016 and due to the low orbital height, it is now inevitable that the Chinese space station will...

Im Focus: Alliance „OLED Licht Forum“ – Key partner for OLED lighting solutions

Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP, provider of research and development services for OLED lighting solutions, announces the founding of the “OLED Licht Forum” and presents latest OLED design and lighting solutions during light+building, from March 18th – 23rd, 2018 in Frankfurt a.M./Germany, at booth no. F91 in Hall 4.0.

They are united in their passion for OLED (organic light emitting diodes) lighting with all of its unique facets and application possibilities. Thus experts in...

Im Focus: Mars' oceans formed early, possibly aided by massive volcanic eruptions

Oceans formed before Tharsis and evolved together, shaping climate history of Mars

A new scenario seeking to explain how Mars' putative oceans came and went over the last 4 billion years implies that the oceans formed several hundred million...

Im Focus: Tiny implants for cells are functional in vivo

For the first time, an interdisciplinary team from the University of Basel has succeeded in integrating artificial organelles into the cells of live zebrafish embryos. This innovative approach using artificial organelles as cellular implants offers new potential in treating a range of diseases, as the authors report in an article published in Nature Communications.

In the cells of higher organisms, organelles such as the nucleus or mitochondria perform a range of complex functions necessary for life. In the networks of...

Im Focus: Locomotion control with photopigments

Researchers from Göttingen University discover additional function of opsins

Animal photoreceptors capture light with photopigments. Researchers from the University of Göttingen have now discovered that these photopigments fulfill an...

All Focus news of the innovation-report >>>



Industry & Economy
Event News

Virtual reality conference comes to Reutlingen

19.03.2018 | Event News

Ultrafast Wireless and Chip Design at the DATE Conference in Dresden

16.03.2018 | Event News

International Tinnitus Conference of the Tinnitus Research Initiative in Regensburg

13.03.2018 | Event News

Latest News

TRAPPIST-1 planets provide clues to the nature of habitable worlds

21.03.2018 | Physics and Astronomy

The search for dark matter widens

21.03.2018 | Materials Sciences

Natural enemies reduce pesticide use

21.03.2018 | Life Sciences

Science & Research
Overview of more VideoLinks >>>