Mutant Protein in Muscle Linked to Neuromuscular Disorder
A new therapeutic target for Kennedy’s disease and a potential treatment
Sometimes known as Kennedy’s disease, spinal and bulbar muscular atrophy (SBMA) is a rare inherited neuromuscular disorder characterized by slowly progressive muscle weakness and atrophy. Researchers have long considered it to be essentially an affliction of primary motor neurons – the cells in the spinal cord and brainstem that control muscle movement.
But in a new study published in the April 16, 2014 online issue of Neuron, a team of scientists at the University of California, San Diego School of Medicine say novel mouse studies indicate that mutant protein levels in muscle cells, not motor neurons, are fundamentally involved in SBMA, suggesting an alternative and promising new avenue of treatment for a condition that is currently incurable.
SBMA is an X-linked recessive disease that affects only males, though females carrying the defective gene have a 50:50 chance of passing it along to a son. It belongs to a group of diseases, such as Huntington’s disease, in which a C-A-G DNA sequence is repeated too many times, resulting in a protein with too many glutamines (an amino acid), causing the diseased protein to misfold and produce harmful consequences for affected cells. Thus far, human clinical trials of treatments to protect against these repeat toxicities have failed.
In the new paper, a team led by principal investigator Albert La Spada, MD, PhD, professor of pediatrics, cellular and molecular medicine, and neurosciences, and the associate director of the Institute for Genomic Medicine at UC San Diego, propose a different therapeutic target. After creating a new mouse model of SBMA, they discovered that skeletal muscle was the site of mutant protein toxicity and that measures which mitigated the protein’s influence in muscle suppressed symptoms of SBMA in treated mice, such as weight loss and progressive weakness, and increased survival.
In a related paper, published in the April 16, 2014 online issue of Cell Reports, La Spada and colleagues describe a potential treatment for SBMA. Currently, there is none.
The scientists developed antisense oligonucleotides – sequences of synthesized genetic material – that suppressed androgen receptor (AR) gene expression in peripheral tissues, but not in the central nervous system. Mutations in the AR gene are the cause of SBMA, a discovery that La Spada made more than 20 years ago while a MD-PhD student.
La Spada said that antisense therapy helped mice modeling SBMA to recover lost muscle weight and strength and extended survival.
“The main points of these papers is that we have identified both a genetic cure and a drug cure for SBMA – at least in mice. The goal now is to further develop and refine these ideas so that we can ultimately test them in people,” La Spada said.
Pictured: striated human skeletal muscle.
Congratulations to our very own Dr. Quyen T. Nguyen, who received the Presidential Early Career Award for Scientists and Engineers (PECASE) at a ceremony in Washington, D.C. yesterday. She received this award for her work testing fluorescently labeled probes for nerve imaging during surgery.
Breaking Bad Mitochondria
Mechanism helps explain persistence of hepatitis C virus
Researchers at the University of California, San Diego School of Medicine have identified a mechanism that explains why people with the hepatitis C virus get liver disease and why the virus is able to persist in the body for so long.
The hard-to-kill pathogen, which infects an estimated 200 million people worldwide, attacks the liver cells’ energy centers – the mitochondria – dismantling the cell’s innate ability to fight infection. It does this by altering cells mitochondrial dynamics.
The study, published in today’s issue of the Proceedings of the National Academy of Sciences, suggests that mitochondrial operations could be a therapeutic target against hepatitis C, the leading cause of liver transplants and a major cause of liver cancer in the U.S.
“Our study tells us the story of how the hepatitis C virus causes liver disease,” said Aleem Siddiqui, PhD, professor of medicine and senior author. “The virus damages mitochondria in liver cells. Cells recognize the damage and respond to it by recruiting proteins that tell the mitochondria to eliminate the damaged area, but the repair process ends up helping the virus.”
Mitochondria are organelles in a cell that convert energy from food (glucose) into a form of energy that can be used by cells called adenosine triphosphate.
Specifically, the researchers discovered that the virus stimulates the production of a protein (Drp 1) that induces viral-damaged mitochondria to undergo asymmetric fragmentation. This fragmentation (fission) results in the formation of one healthy mitochondrion and one damaged or bad mitochondrion, the latter of which is quickly broken down (catabolized) and dissolved in the cell’s cytoplasm.
Pictured: Mitochondria in hepatitis C-infected cells (bottom row) are self-destructing. The self-annihilation process explains the persistance and virulence of the virus in human liver cells.
For Entamoeba histolytica, that’s dinner up above, otherwise known as the human intestine. Cousin to the brain-munching Naegleria fowleri, E. histolytica resides in your gut, where it can cause a long-lasting and severe case of “food poisoning.” Millions of cases of dysentery and colitis are attributed each year to this common single-celled animal.
Recently, scientists figured out how exactly the pathogen wreaks havoc and, well, it’s gross: It bites off little bits of intestine, chews them up and spits them out. The process is called trogocytosis, derived in part from the Greek word trogo, which means “to nibble.”
E. histolytica’s lifestyle is a bit confusing. Other gut-churning pathogens, like Escherichia coli, do their worst by secreting toxins. N. fowleri triggers a harmful inflammatory response, one that can result in deadly encephalitis. E. histolytica’s approach seems a bit over-dramatic, but some researchers suggest chewing out chunks of the intestinal wall might be useful in creating more room to grow and reproduce.
Pictured: A biopsy of the human small intestine as seen through a confocal laser scanning microscope. Intestinal epithelium has been stained blue, with cell nuclei in red.
Splice Variants Reveal Connections Among Autism Genes
A team of researchers from the University of California, San Diego School of Medicine and the Center for Cancer Systems Biology (CCSB) at the Dana-Farber Cancer Institute has uncovered a new aspect of autism, revealing that proteins involved in autism interact with many more partners than previously known. These interactions had not been detected earlier because they involve alternatively spliced forms of autism genes found in the brain.
In their study, published in the April 11, 2014 online issue of Nature Communications, the scientists isolated hundreds of new variants of autism genes from the human brain, and then screened their protein products against thousands of other proteins to identify interacting partners. Proteins produced by alternatively-spliced autism genes and their many partners formed a biological network that produced an unprecedented view of how autism genes are connected.
"When the newly discovered splice forms of autism genes were added to the network, the total number of interactions doubled," said principal investigator Lilia Iakoucheva, PhD, assistant professor in the Department of Psychiatry at UC San Diego. In some cases, the splice forms interacted with a completely different set of proteins. "What we see from this network is that different variants of the same protein could alter the wiring of the entire system," Iakoucheva said.
"This is the first proteome-scale interaction network to incorporate alternative splice forms," noted Marc Vidal, PhD, CCSB director and a co-investigator on the study. "The fact that protein variants produce such diverse patterns of interactions is exciting and quite unexpected."
The new network also illuminated how multiple autism genes connect to one another. The scientists found that one class of mutations involved in autism, known as copy number variants, involve genes that are closely connected to each other directly or indirectly through a common partner. “This suggests that shared biological pathways may be disrupted in patients with different autism mutations,” said co-first author Guan Ning Lin, PhD, a postdoctoral fellow in Iakouchevaís laboratory.
Beyond providing greater breadth and depth around autism proteins, the network represents a new resource for future autism studies, according to Iakoucheva. For example, she said the physical collection of more than 400 splicing variants of autism candidate genes could be used by other researchers interested in studying a specific protein variant. Some of the highly connected network partners may also represent potential drug targets. All interaction data will reside in the publicly available National Database of Autism Research.
"With this assembled autism network, we can begin to investigate how newly discovered mutations from patients may disrupt this network,î said Iakoucheva. "This is an important task because the mechanism by which mutant proteins contribute to autism in 99.9 percent of cases remains unknown."
Pictured: Splicing variants (red) of autism genes were cloned from the brain and screened for interactions. The image on the right represents the network of interactions. Gray lines are interactions from a single isoform; red lines are interactions from additional isoforms of autism candidate genes (yellow circles).
UC San Diego Researcher to Lead a NASA Identical Twin Study
Brinda Rana, PhD, a professor at the University of California, San Diego School of Medicine, has been awarded NASA funding to study the effects of near-zero gravity on fluid flows in the brain.
Her project, one of 10 funded through NASA’s $1.5-million twin astronaut study, will look at how space flight affects fluid pressure in the brain and its implications for vision.
“Our bodies are adapted to an environment in which gravity pools fluids toward our legs,” Rana said. “In space, fluid flows upward. Our project will examine the effects of spaceflight on the proteins that regulate vasoconstriction and dilation, and fluid regulation.”
“Like other NASA innovations, such as memory foam and cordless tools, these studies could potentially impact health care on Earth,” Rana said.
The project that she is leading, for example, may shed light on potential new treatments for traumatic brain injury, glaucoma and “water on the brain.”
Only one set of twins – astronauts Scott and Mark Kelly – has ever been to space, making them “an unprecedented opportunity” for scientists to study the physiological and molecular effects of space flight, NASA officials say.
“Studying identical twins enable us to control for 100 percent of genetic factors and shared environmental factors,” Rana said.
In March 2015, Scott will begin a one-year stay on the International Space Station while his brother, Mark, will remain on Earth and serve as “ground control.”
Blood and urine samples will be collected from the twins before, during and after the mission to search for genetic, proteomic (protein-related), metabolomic and molecular markers of the effects of – and adaptations to – space flight.
The standard stay on the space station is approximately six months. No human has ever lived in space for an entire year. For those who still dream of manned space explorations of, say, Mars, where evidence of flowing, liquid water was recently reported, the projects will gather the type of information needed for more distant explorations of the solar system.
“NASA needs to understand the long-term impact of these missions in order to identify strategies to monitor health outcomes and reduce health risks,” she said.
Rana is also a co-investigator on a project led by Stuart Lee, a lead research scientist for Wyle Integrated Science and Engineering at NASA Johnson Space Center’s Cardiovascular Laboratory, which focuses on understanding the effects of space on heart health.
Other projects funded through the twin study will examine the effects of near-zero gravity, radiation and other space-related environmental stressors on gut flora, immune function and the aging process.
UC San Diego co-investigators on the projects include Kumar Sharma, MD, Alan Hargens, PhD, Vivian Hook, PhD, Brandon Macias, PhD, and Dorothy Sears, PhD.
Is that just about the most adorable, little power plant you’ve ever seen?
OK, he’s just a baby now, but if researchers at Penn State are ultimately successful, someday we might all be able to tap into a new – and in the case of babies, seemingly inexhaustible – supply of energy from saliva.
Penn State engineers recently reported creating a tiny microbial fuel cell capable of producing enough power from human spit to run on-chip applications. The fuel cell creates energy when bacteria break down organic matter in saliva, generating a charge that is transferred to the anode.
The microbial fuel cell produced almost 1 microwatt (one millionth of a watt) of power. That’s not a lot by most measures – the human brain’s daily electrical output is 20 watts, enough to illuminate a small refrigerator – but it could be sufficient for future applications, like a proposed ovulation predictor based on the electrical conductivity of a woman’s saliva, which changes five days before ovulation. The predictor would send a signal to a nearby cell phone, alerting the woman.
For Good and Ill, Immune Response to Cancer Cuts Both Ways -
The difference between an immune response that kills cancer cells and one that conversely stimulates tumor growth can be as narrow as a “double-edged sword,” report researchers at the University of California, San Diego School of Medicine in the April 7, 2014 online issue of the Proceedings of the National Academy of Sciences.
“We have found that the intensity difference between an immune response that stimulates cancer and one that kills it may not be very much,” said principal investigator Ajit Varki, MD, Distinguished Professor of Medicine and Cellular and Molecular Medicine. “This may come as a surprise to researchers exploring two areas typically considered distinct: the role of the immune system in preventing and killing cancers and the role of chronic inflammation in stimulating cancers. As always, it turns out that the immune system is a double-edged sword.”
The concept of naturally occurring “immunosurveillance” against malignancies is not new, and there is compelling evidence for it. But understanding this process is confounded by the fact that some types of immune reaction promote tumor development. Varki and colleagues looked specifically at a non-human sialic acid sugar molecule called Neu5Gc. Previous research has found that Neu5Gc accumulates in human tumors from dietary sources, despite an on-going antibody response against it.
The scientists deployed antibodies against Neu5Gc in a human-like mouse tumor model to determine whether and to what degree the antibodies altered tumor progression. They found that low antibody doses stimulated growth, but high doses inhibited it. The effect occurred over a “linear and remarkably narrow range,” said Varki, generating an immune response curve or “inverse hormesis.” Moreover, this curve could be shifted to the left or right simply by modifying the quality of the immune response.
Similar findings were made in experiments with two other mouse tumor models, and with a human tumor xenograft model using a monoclonal antibody currently in clinical use. The scientists concluded that the difference in intensity between an immune response stimulating tumors and one that kills them may be much less than previously imagined.
Varki said the results may have implications for all aspects of cancer science, from studying its causes to prevention and treatment. This is because the immune response can have multiple roles in the genesis of cancers, in altering the progress of established tumors and in anti-cancer therapies that use antibodies as drugs.
UC San Diego Health Sciences News turned 3 today!
Happy 3rd Blogday to Us!
Today marks our third anniversary on tumblr – three years of discovery, expert advice and occasional moments of frivolity.
Some of the things we’ve done in those three years:
Gone from a handful of followers to over 69,500 as of this posting (!!)
Posted 120 weekly Science in Photos features
Offered over 50 Q & As with our experts on relevant health issues, such as how to navigate the changing guidelines for prostate cancer screenings to mammogram standards to effects of bath salts to the occurrence of stroke in young adults.
And we’ve had some fun, too! From hijacking the zombie apocalypse to speak about disaster preparedness to touting our Super Heroes of Medicine to highlighting members of our team who helped deliver a baby gorilla – there’s more to science and medicine than dry research papers, after all.
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