Scientists show bad androgen receptor impairs body's ability to dispose of damaged cells
Researchers at University of California, San Diego School of Medicine have identified the mechanism by which a rare, inherited neurodegenerative disease causes often crippling muscle weakness in men, in addition to reduced fertility.
The study, published August 10 in the journal Nature Neuroscience, shows that a gene mutation long recognized as a key to the development of Kennedy's disease impairs the body's ability to degrade, remove and recycle clumps of "trash" proteins that may otherwise build up on neurons, progressively impairing their ability to control muscle contraction. This mechanism, called autophagy, is akin to a garbage disposal system and is the only way for the body to purge itself of non-working, misshapen trash proteins.
"We've known since the mid-1990s that Alzheimer's disease, Parkinson's disease and Huntington's disease are caused by the accumulation of misfolded proteins that should have been degraded, but cannot be turned over," said senior author Albert La Spada, MD, PhD and professor of pediatrics, cellular and molecular medicine, and neurosciences. "The value of this study is that it identifies a target for halting the progression of protein build-up, not just in this rare disease, but in many other diseases that are associated with impaired autophagy pathway function."
Of the 400 to 500 men in the U.S. with Kennedy's disease, the slow but progressive loss of motor function results in about 15 to 20 percent of those with the disease becoming wheel-chair bound during later stages of the disease.
Kennedy's disease, also known as spinal and bulbar muscular atrophy, is a recessive X-linked disease men inherit from their mother. Women don't get the disease because they have two copies of the X chromosome. The genetic abnormality causes men to produce a mutant androgen receptor protein, which impairs the body's sensitivity and response to male sex hormones, sometimes resulting in testicular atrophy and enlargement of male breasts.
In experiments with mice, scientists discovered that the mutant androgen receptor protein besides disrupting male reproductive biology also deactivates a protein called transcription factor EB (TFEB) that is believed to be a master regulator of autophagy in nerve and other cell types.
Specifically, the mutant androgen receptor protein in Kennedy's disease binds to TFEB and blocks its ability to mediate the break-down and removal of non-working proteins and aggregated proteins.
"Our study tells us that if we can find a way to keep TFEB working, we likely can prevent this disease and others like it from progressing," La Spada said. "We now have a target for new therapies to treat not only Kennedy's disease, but also many more common neurological disorders."
Co-authors include Constanza J. Cortes, Helen C Miranda, Harald Frankowski, Yakup Batlevi, Jessica E. Young, Amy Le and Cassiano Carromeu, UC San Diego; Nishi Ivanov, Bryce L. Sopher and Gwenn A. Garden, University of Washington; and Alysson R. Muotri, UC San Diego and Rady Children's Hospital-San Diego.
Funding for this study was provided by the National Institutes of Health (R01 NS041648, R01 AG033082 and DP2-OD006495-01), Muscular Dystrophy Association and the California Institute for Regenerative Medicine.
Jackie Carr | Eurek Alert!
Mobile phone test can reveal vision problems in time
11.02.2016 | University of Gothenburg
Proteomics and precision medicine
08.02.2016 | University of Iowa Health Care
Today, plants and microorganisms are heavily used for the production of medicinal products. The production of biopharmaceuticals in plants, also referred to as “Molecular Pharming”, represents a continuously growing field of plant biotechnology. Preferred host organisms include yeast and crop plants, such as maize and potato – plants with high demands. With the help of a special algal strain, the research team of Prof. Ralph Bock at the Max Planck Institute of Molecular Plant Physiology in Potsdam strives to develop a more efficient and resource-saving system for the production of medicines and vaccines. They tested its practicality by synthesizing a component of a potential AIDS vaccine.
The use of plants and microorganisms to produce pharmaceuticals is nothing new. In 1982, bacteria were genetically modified to produce human insulin, a drug...
Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock which attains an accuracy which had only been predicted theoretically so far. Their optical ytterbium clock achieved a relative systematic measurement uncertainty of 3 E-18. The results have been published in the current issue of the scientific journal "Physical Review Letters".
Atomic clock experts from the Physikalisch-Technische Bundesanstalt (PTB) are the first research group in the world to have built an optical single-ion clock...
The University of Würzburg has two new space projects in the pipeline which are concerned with the observation of planets and autonomous fault correction aboard satellites. The German Federal Ministry of Economic Affairs and Energy funds the projects with around 1.6 million euros.
Detecting tornadoes that sweep across Mars. Discovering meteors that fall to Earth. Investigating strange lightning that flashes from Earth's atmosphere into...
Physicists from Saarland University and the ESPCI in Paris have shown how liquids on solid surfaces can be made to slide over the surface a bit like a bobsleigh on ice. The key is to apply a coating at the boundary between the liquid and the surface that induces the liquid to slip. This results in an increase in the average flow velocity of the liquid and its throughput. This was demonstrated by studying the behaviour of droplets on surfaces with different coatings as they evolved into the equilibrium state. The results could prove useful in optimizing industrial processes, such as the extrusion of plastics.
The study has been published in the respected academic journal PNAS (Proceedings of the National Academy of Sciences of the United States of America).
Exceeding critical temperature limits in the Southern Ocean may cause the collapse of ice sheets and a sharp rise in sea levels
A future warming of the Southern Ocean caused by rising greenhouse gas concentrations in the atmosphere may severely disrupt the stability of the West...
09.02.2016 | Event News
02.02.2016 | Event News
26.01.2016 | Event News
11.02.2016 | Life Sciences
11.02.2016 | Physics and Astronomy
11.02.2016 | Earth Sciences