Mutant Protein in Muscle Linked to Neuromuscular DisorderA 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.

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.

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).

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.

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.

UC San Diego researchers have found clear and direct new evidence that autism begins during pregnancy, reporting that patches of disrupted brain development occur in the womb.

Patches of Cortical Layers Disrupted During Early Brain Development in Autism

Researchers at the University of California, San Diego School of Medicine and the Allen Institute for Brain Science have published a study that gives clear and direct new evidence that autism begins during pregnancy.

The study will be published in the March 27 online edition of the New England Journal of Medicine.  

The researchers – Eric Courchesne, PhD, professor of neurosciences and director of the Autism Center of Excellence at UC San Diego, Ed S. Lein, PhD, of the Allen Institute for Brain Science in Seattle, and first author Rich Stoner, PhD, of the UC San Diego Autism Center of Excellence – analyzed 25 genes in post-mortem brain tissue of children with and without autism. These included genes that serve as biomarkers for brain cell types in different layers of the cortex, genes implicated in autism and several control genes.

“Building a baby’s brain during pregnancy involves creating a cortex that contains six layers,” Courchesne said. “We discovered focal patches of disrupted development of these cortical layers in the majority of children with autism.” Stoner created the first three-dimensional model visualizing brain locations where patches of cortex had failed to develop the normal cell-layering pattern.

“The most surprising finding was the similar early developmental pathology across nearly all of the autistic brains, especially given the diversity of symptoms in patients with autism, as well as the extremely complex genetics behind the disorder,” explained Lein.

During early brain development, each cortical layer develops its own specific types of brain cells, each with specific patterns of brain connectivity that perform unique and important roles in processing information. As a brain cell develops into a specific type in a specific layer with   specific connections, it acquires a distinct genetic signature or “marker” that can be observed.

The study found that in the brains of children with autism, key genetic markers were absent in brain cells in multiple layers. “This defect,” Courchesne said, “indicates that the crucial early developmental step of creating six distinct layers with specific types of brain cells – something that begins in prenatal life – had been disrupted.”

Equally important, said the scientists, these early developmental defects were present in focal patches of cortex, suggesting the defect is not uniform throughout the cortex. The brain regions most affected by focal patches of absent gene markers were the frontal and the temporal cortex, possibly illuminating why different functional systems are impacted across individuals with the disorder.

The frontal cortex is associated with higher-order brain function, such as complex communication and comprehension of social cues. The temporal cortex is associated with language. The disruptions of frontal and temporal cortical layers seen in the study may underlie symptoms most often displayed in autistic spectrum disorders. The visual cortex – an area of the brain associated with perception that tends to be spared in autism – displayed no abnormalities. 

“The fact that we were able to find these patches is remarkable, given that the cortex is roughly the size of the surface of a basketball, and we only examined pieces of tissue the size of a pencil eraser,” said Lein. “This suggests that these abnormalities are quite pervasive across the surface of the cortex.”

Data collected for the Allen Brain Atlas, as well as the BrainSpan Atlas of the Developing Human Brain was developed by a consortium of partners and funded by the National Institute of Mental Health. It allowed scientists to identify specific genes in the developing human brain that could be used as biomarkers for the different layer cell types.

Researching the origins of autism is challenging because it typically relies upon studying adult brains and attempting to extrapolate backwards. “In this case,” Lein noted, “we were able to study autistic and control cases at a young age, giving us a unique insight into how autism presents in the developing brain.”

“The finding that these defects occur in patches rather than across the entirety of cortex gives hope as well as insight about the nature of autism,” added Courchesne.

According to the scientists, such patchy defects, as opposed to uniform cortical pathology, may help explain why many toddlers with autism show clinical improvement with early treatment and over time. The findings support the idea that in children with autism the brain can sometimes rewire connections to circumvent early focal defects, raising hope that understanding these patches may eventually open new avenues to explore how that improvement occurs.

A coronary aneurysm is an abnormal ballooning of a portion of the coronary artery and a potential consequence of Kawasaki disease. If untreated, it may result in irreversible heart damage and death. This angiography of an 18-year-old patient reveals a massive aneurysm in the right coronary artery compared to the normal left. Image courtesy of Tomio Kobayashi, Gunma University School of Medicine, Japan.
Study Evaluates Role of Infliximab in Treating Kawasaki DiseaseAntibody treatment helps children with dangerous heart disorder
Kawasaki Disease (KD) is a severe childhood disease that many parents, even some doctors, mistake for an inconsequential viral infection. If not diagnosed or treated in time, it can lead to irreversible heart damage.
Signs of KD include prolonged fever associated with rash, red eyes, mouth, lips and tongue, and swollen hands and feet with peeling skin. The disease causes damage to the coronary arteries in a quarter of untreated children and may lead to serious heart problems in early adulthood. There is no diagnostic test for Kawasaki disease, and current treatment fails to prevent coronary artery damage in at least one in 10 to 20 children and death in one in 1,000 children. 
Between 10 and 20 percent of patients with KD experience fever relapse following the standard therapy with a single infusion of intravenous immunoglobulin (IVIG) and aspirin. It is known that IVIG resistance increases the risk of heart damage, most commonly a ballooning of the coronary arteries called aneurysms. These children require additional therapy to interrupt the inflammatory process that can lead to damage of the coronary arteries.
A study led by physicians at the University of California, San Diego School of Medicine and Rady Children’s Hospital-San Diego looked at intensification of initial therapy for all children with KD in order to prevent IVIG-resistance and associated coronary artery abnormalities by assessing the addition of the medication infliximab to current standard therapy. The results of their study will be published in the February 24, 2014 online issue of the medical journal Lancet. 
More here

A coronary aneurysm is an abnormal ballooning of a portion of the coronary artery and a potential consequence of Kawasaki disease. If untreated, it may result in irreversible heart damage and death. This angiography of an 18-year-old patient reveals a massive aneurysm in the right coronary artery compared to the normal left. Image courtesy of Tomio Kobayashi, Gunma University School of Medicine, Japan.

Study Evaluates Role of Infliximab in Treating Kawasaki Disease
Antibody treatment helps children with dangerous heart disorder

Kawasaki Disease (KD) is a severe childhood disease that many parents, even some doctors, mistake for an inconsequential viral infection. If not diagnosed or treated in time, it can lead to irreversible heart damage.

Signs of KD include prolonged fever associated with rash, red eyes, mouth, lips and tongue, and swollen hands and feet with peeling skin. The disease causes damage to the coronary arteries in a quarter of untreated children and may lead to serious heart problems in early adulthood. There is no diagnostic test for Kawasaki disease, and current treatment fails to prevent coronary artery damage in at least one in 10 to 20 children and death in one in 1,000 children. 

Between 10 and 20 percent of patients with KD experience fever relapse following the standard therapy with a single infusion of intravenous immunoglobulin (IVIG) and aspirin. It is known that IVIG resistance increases the risk of heart damage, most commonly a ballooning of the coronary arteries called aneurysms. These children require additional therapy to interrupt the inflammatory process that can lead to damage of the coronary arteries.

A study led by physicians at the University of California, San Diego School of Medicine and Rady Children’s Hospital-San Diego looked at intensification of initial therapy for all children with KD in order to prevent IVIG-resistance and associated coronary artery abnormalities by assessing the addition of the medication infliximab to current standard therapy. The results of their study will be published in the February 24, 2014 online issue of the medical journal Lancet

More here

Model organism Caenorhabditis elegans.
Global Regulator of mRNA Editing FoundProtein controls editing, expanding the information content of DNA
An international team of researchers, led by scientists from the University of California, San Diego School of Medicine and Indiana University, have identified a protein that broadly regulates how genetic information transcribed from DNA to messenger RNA (mRNA) is processed and ultimately translated into the myriad of proteins necessary for life.
The findings, published today in the journal Cell Reports, help explain how a relatively limited number of genes can provide versatile instructions for making thousands of different messenger RNAs and proteins used by cells in species ranging from sea anemones to humans. In clinical terms, the research might also help researchers parse the underlying genetic mechanisms of diverse diseases, perhaps revealing new therapeutic targets.
“Problems with RNA editing show up in many human diseases, including those of neurodegeneration, cancer and blood disorders,” said Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine at UC San Diego. “This is the first time that a single protein has been identified that broadly regulates RNA editing. There are probably hundreds more. Our approach provides a method to screen for them and opens up new ways to study human biology and disease.”
“To be properly expressed, all genes must be carefully converted from DNA to messenger RNA, which can then be translated into working proteins,” said Heather Hundley, PhD, assistant professor of biochemistry and molecular biology at Indiana University and co-senior author of the study. RNA editing alters nucleotides (the building blocks of DNA and RNA) within the mRNA to allow a single gene to create multiple mRNAs that are subject to different modes of regulation. How exactly this process can be modulated, however, has never been clear.
Using the nematode Caenorhabditis elegans as their model organism and a novel computational framework, Hundley, Yeo and colleagues identified more than 400 new mRNA editing sites – the majority regulated by a single protein called ADR-1, which does not directly edit mRNA but rather regulated how editing occurred by binding to the messenger RNAs subject to editing.
“Cells process their genetic code in a way analogous to how the programming language Java compiles modern software. Both systems use an intermediate representation that is modified depending on its environment” said co-first author Boyko Kakaradov, a bioinformatics PhD student in the Yeo lab. “We’re now finding how and why the mRNA code is being changed en route to the place of execution.”
The scientists noted that a protein similar to ADR-1 is expressed by humans, and that many of the same mRNA targets exist in people too. “So it is likely that a similar mechanism exists to regulate editing in humans,” said Hundley, adding that she and colleagues will now turn to teasing out the specifics of how proteins like ADR-1 regulate editing and how they might be exploited “to modulate editing for the treatment of human diseases.”  

Model organism Caenorhabditis elegans.

Global Regulator of mRNA Editing Found
Protein controls editing, expanding the information content of DNA

An international team of researchers, led by scientists from the University of California, San Diego School of Medicine and Indiana University, have identified a protein that broadly regulates how genetic information transcribed from DNA to messenger RNA (mRNA) is processed and ultimately translated into the myriad of proteins necessary for life.

The findings, published today in the journal Cell Reports, help explain how a relatively limited number of genes can provide versatile instructions for making thousands of different messenger RNAs and proteins used by cells in species ranging from sea anemones to humans. In clinical terms, the research might also help researchers parse the underlying genetic mechanisms of diverse diseases, perhaps revealing new therapeutic targets.

“Problems with RNA editing show up in many human diseases, including those of neurodegeneration, cancer and blood disorders,” said Gene Yeo, PhD, assistant professor in the Department of Cellular and Molecular Medicine at UC San Diego. “This is the first time that a single protein has been identified that broadly regulates RNA editing. There are probably hundreds more. Our approach provides a method to screen for them and opens up new ways to study human biology and disease.”

“To be properly expressed, all genes must be carefully converted from DNA to messenger RNA, which can then be translated into working proteins,” said Heather Hundley, PhD, assistant professor of biochemistry and molecular biology at Indiana University and co-senior author of the study. RNA editing alters nucleotides (the building blocks of DNA and RNA) within the mRNA to allow a single gene to create multiple mRNAs that are subject to different modes of regulation. How exactly this process can be modulated, however, has never been clear.

Using the nematode Caenorhabditis elegans as their model organism and a novel computational framework, Hundley, Yeo and colleagues identified more than 400 new mRNA editing sites – the majority regulated by a single protein called ADR-1, which does not directly edit mRNA but rather regulated how editing occurred by binding to the messenger RNAs subject to editing.

“Cells process their genetic code in a way analogous to how the programming language Java compiles modern software. Both systems use an intermediate representation that is modified depending on its environment” said co-first author Boyko Kakaradov, a bioinformatics PhD student in the Yeo lab. “We’re now finding how and why the mRNA code is being changed en route to the place of execution.”

The scientists noted that a protein similar to ADR-1 is expressed by humans, and that many of the same mRNA targets exist in people too. “So it is likely that a similar mechanism exists to regulate editing in humans,” said Hundley, adding that she and colleagues will now turn to teasing out the specifics of how proteins like ADR-1 regulate editing and how they might be exploited “to modulate editing for the treatment of human diseases.”  

CLL cells, Wellcome Images. 
The Mouse That ROR’edROR1 oncogene combines with another to accelerate, worsen blood cancer
Researchers at the University of California, San Diego School of Medicine report that an oncogene dubbed ROR1, found on chronic lymphocytic leukemia (CLL) B cells but not normal adult tissues, acts as an accelerant when combined with another oncogene, resulting in a faster-developing, more aggressive form of CLL in mice.
The findings, published in the Dec. 30, 2013 Online Early Edition of PNAS, suggest ROR1 could be an important therapeutic target for patients with CLL, the most common form of blood cancer. Prevalence of CLL in the United States is high: 1 in 20 people over the age of 40 could  have apparently pre-cancerous CLL-like cells in their blood. These people may develop actual CLL at a rate of about 1 percent per year. More than 15,000 new cases of CLL are diagnosed each year in the United States. Roughly 4,400 patients with CLL die annually.
The work by principal investigator Thomas Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research, and colleagues continues a series of discoveries about ROR1. Previously, for example, they found an association between ROR1 and the epithelial-mesenchymal transition – the process that occurs during embryogenesis when cells migrate and then grow into new organs during early development. CLL cells exploit ROR1 to spread disease. Called metastasis, it is responsible for 90 percent of cancer-related deaths.
In the PNAS paper, Kipps and colleagues created transgenic mice that expressed human ROR1, then observed that these mice produced B cells (a kind of white blood cell) that were abnormal and resembled human CLL cells while non-transgenic littermates did not.
Next they crossed the ROR1 mice with another transgenic mouse-type that produces an oncogene called TCL1. Oncogenes are genes that can lead to cancer development if over-expressed or mutated. The progeny of these cross-bred mice possessed both oncogenes – ROR1 and TCL1 – and consequently displayed an even greater proclivity toward developing aggressive, fast-acting CLL.
When researchers treated the mice with an anti-ROR1 monoclonal antibody that reduces levels of ROR1, the CLL cells were impaired and more vulnerable to treatment and destruction.  Based on these findings, Kipps said investigators at UC San Diego Moores Cancer Center are planning clinical trials in 2014 using a humanized monoclonal antibody that has the same type of activity against human leukemia or cancer cells that express ROR1.

CLL cells, Wellcome Images.

The Mouse That ROR’ed
ROR1 oncogene combines with another to accelerate, worsen blood cancer

Researchers at the University of California, San Diego School of Medicine report that an oncogene dubbed ROR1, found on chronic lymphocytic leukemia (CLL) B cells but not normal adult tissues, acts as an accelerant when combined with another oncogene, resulting in a faster-developing, more aggressive form of CLL in mice.

The findings, published in the Dec. 30, 2013 Online Early Edition of PNAS, suggest ROR1 could be an important therapeutic target for patients with CLL, the most common form of blood cancer. Prevalence of CLL in the United States is high: 1 in 20 people over the age of 40 could  have apparently pre-cancerous CLL-like cells in their blood. These people may develop actual CLL at a rate of about 1 percent per year. More than 15,000 new cases of CLL are diagnosed each year in the United States. Roughly 4,400 patients with CLL die annually.

The work by principal investigator Thomas Kipps, MD, PhD, Evelyn and Edwin Tasch Chair in Cancer Research, and colleagues continues a series of discoveries about ROR1. Previously, for example, they found an association between ROR1 and the epithelial-mesenchymal transition – the process that occurs during embryogenesis when cells migrate and then grow into new organs during early development. CLL cells exploit ROR1 to spread disease. Called metastasis, it is responsible for 90 percent of cancer-related deaths.

In the PNAS paper, Kipps and colleagues created transgenic mice that expressed human ROR1, then observed that these mice produced B cells (a kind of white blood cell) that were abnormal and resembled human CLL cells while non-transgenic littermates did not.

Next they crossed the ROR1 mice with another transgenic mouse-type that produces an oncogene called TCL1. Oncogenes are genes that can lead to cancer development if over-expressed or mutated. The progeny of these cross-bred mice possessed both oncogenes – ROR1 and TCL1 – and consequently displayed an even greater proclivity toward developing aggressive, fast-acting CLL.

When researchers treated the mice with an anti-ROR1 monoclonal antibody that reduces levels of ROR1, the CLL cells were impaired and more vulnerable to treatment and destruction.  Based on these findings, Kipps said investigators at UC San Diego Moores Cancer Center are planning clinical trials in 2014 using a humanized monoclonal antibody that has the same type of activity against human leukemia or cancer cells that express ROR1.

How Cells Remodel After UV RadiationResearchers map cell’s complex genetic interactions to fix damaged DNA 
Researchers at the University of California, San Diego School of Medicine, with colleagues in The Netherlands and United Kingdom, have produced the first map detailing the network of genetic interactions underlying the cellular response to ultraviolet (UV) radiation.
The researchers say their study establishes a new method and resource for exploring in greater detail how cells are damaged by UV radiation and how they repair themselves. UV damage is one route to malignancy, especially in skin cancer, and understanding the underlying repair pathways will better help scientists to understand what goes wrong in such cancers.
The findings will be published in the December 26, 2013 issue of Cell Reports.
Principal investigator Trey Ideker, PhD, division chief of genetics in the UC San Diego School of Medicine and a professor in the UC San Diego Departments of Medicine and Bioengineering, and colleagues mapped 89 UV-induced functional interactions among 62 protein complexes. The interactions were culled from a larger measurement of more than 45,000 double mutants, the deletion of two separate genes, before and after different doses of UV radiation.
Specifically, they identified interactive links to the cell’s chromatin structure remodeling (RSC) complex, a grouping of protein subunits that remodel chromatin – the combination of DNA and proteins that make up a cell’s nucleus – during cell mitosis or division. “We show that RSC is recruited to places on genes or DNA sequences where UV damage has occurred and that it helps facilitate efficient repair by promoting nucleosome remodeling,” said Ideker.
The process of repairing DNA damage caused by UV radiation and other sources, such as chemicals and other mutagens, is both simple and complicated. DNA-distorting lesions are detected by a cellular mechanism called the nucleotide excision repair (NER) pathway. The lesion is excised; the gap filled with new genetic material copied from an intact DNA strand by special enzymes; and the remaining nick sealed by another specialized enzyme.
However, NER does not work in isolation; rather it coordinates with other biological mechanisms, including RSC.
“DNA isn’t free-floating in the cell, but is packaged into a tight structure called chromatin, which is DNA wound around proteins,” said Rohith Srivas, PhD, a former research scientist in Ideker’s lab and the study’s first author. “In order for repair factors to fix DNA damage, they need access to naked DNA. This is where chromatin remodelers come in: In theory, they can be recruited to the DNA, open it up and allow repair factors to do their job.”
Rohith said that other scientists have previously identified complexes that perform this role following UV damage. “Our results are novel because they show RSC is connected to both UV damage pathways: transcription coupled repair – which acts on parts of DNA being expressed – and global genome repair, which acts everywhere. All previous remodelers were linked only to global genome repair.”
The scientists noted that the degree of genetic rewiring correlates with the dose of UV. Reparative interactions were observed at distinct low or high doses of UV, but not both.  While genetic interactions at higher doses is not surprising, the authors said, the findings suggest low-dose UV radiation prompts specific interactions as well.

How Cells Remodel After UV Radiation
Researchers map cell’s complex genetic interactions to fix damaged DNA

Researchers at the University of California, San Diego School of Medicine, with colleagues in The Netherlands and United Kingdom, have produced the first map detailing the network of genetic interactions underlying the cellular response to ultraviolet (UV) radiation.

The researchers say their study establishes a new method and resource for exploring in greater detail how cells are damaged by UV radiation and how they repair themselves. UV damage is one route to malignancy, especially in skin cancer, and understanding the underlying repair pathways will better help scientists to understand what goes wrong in such cancers.

The findings will be published in the December 26, 2013 issue of Cell Reports.

Principal investigator Trey Ideker, PhD, division chief of genetics in the UC San Diego School of Medicine and a professor in the UC San Diego Departments of Medicine and Bioengineering, and colleagues mapped 89 UV-induced functional interactions among 62 protein complexes. The interactions were culled from a larger measurement of more than 45,000 double mutants, the deletion of two separate genes, before and after different doses of UV radiation.

Specifically, they identified interactive links to the cell’s chromatin structure remodeling (RSC) complex, a grouping of protein subunits that remodel chromatin – the combination of DNA and proteins that make up a cell’s nucleus – during cell mitosis or division. “We show that RSC is recruited to places on genes or DNA sequences where UV damage has occurred and that it helps facilitate efficient repair by promoting nucleosome remodeling,” said Ideker.

The process of repairing DNA damage caused by UV radiation and other sources, such as chemicals and other mutagens, is both simple and complicated. DNA-distorting lesions are detected by a cellular mechanism called the nucleotide excision repair (NER) pathway. The lesion is excised; the gap filled with new genetic material copied from an intact DNA strand by special enzymes; and the remaining nick sealed by another specialized enzyme.

However, NER does not work in isolation; rather it coordinates with other biological mechanisms, including RSC.

“DNA isn’t free-floating in the cell, but is packaged into a tight structure called chromatin, which is DNA wound around proteins,” said Rohith Srivas, PhD, a former research scientist in Ideker’s lab and the study’s first author. “In order for repair factors to fix DNA damage, they need access to naked DNA. This is where chromatin remodelers come in: In theory, they can be recruited to the DNA, open it up and allow repair factors to do their job.”

Rohith said that other scientists have previously identified complexes that perform this role following UV damage. “Our results are novel because they show RSC is connected to both UV damage pathways: transcription coupled repair – which acts on parts of DNA being expressed – and global genome repair, which acts everywhere. All previous remodelers were linked only to global genome repair.”

The scientists noted that the degree of genetic rewiring correlates with the dose of UV. Reparative interactions were observed at distinct low or high doses of UV, but not both.  While genetic interactions at higher doses is not surprising, the authors said, the findings suggest low-dose UV radiation prompts specific interactions as well.

Confocal image of an Alzheimer’s brain showing region of amyloid plaque. Courtesy of Wellcome Images. 
Understanding a Protein’s Role in Familial Alzheimer’s DiseaseNovel genomic approach reveals gene mutation isn’t simple answer
Researchers at the University of California, San Diego School of Medicine have used genetic engineering of human induced pluripotent stem cells to specifically and precisely parse the roles of a key mutated protein in causing familial Alzheimer’s disease (AD), discovering that simple loss-of-function does not contribute to the inherited form of the neurodegenerative disorder.
The findings, published online in the journal Cell Reports, could help elucidate the still-mysterious mechanisms of Alzheimer’s disease and better inform development of effective drugs, said principal investigator Lawrence Goldstein, PhD, professor in the Departments of Cellular and Molecular Medicine and Neurosciences and director of the UC San Diego Stem Cell Program.
“In some ways, this is a powerful technical demonstration of the promise of stem cells and genomics research in better understanding and ultimately treating AD,” said Goldstein, who is also director of the new Sanford Stem Cell Clinical Center at UC San Diego. “We were able to identify and assign precise limits on how a mutation works in familial AD. That’s an important step in advancing the science, in finding drugs and treatments that can slow, maybe reverse, the disease’s devastating effects.”
Familial AD is a subset of early-onset Alzheimer’s disease that is caused by inherited gene mutations. Most cases of Alzheimer’s disease – there are an estimated 5.2 million Americans with AD – are sporadic and do not have a precise known cause, though age is a primary risk factor.    
More here

Confocal image of an Alzheimer’s brain showing region of amyloid plaque. Courtesy of Wellcome Images.

Understanding a Protein’s Role in Familial Alzheimer’s Disease
Novel genomic approach reveals gene mutation isn’t simple answer

Researchers at the University of California, San Diego School of Medicine have used genetic engineering of human induced pluripotent stem cells to specifically and precisely parse the roles of a key mutated protein in causing familial Alzheimer’s disease (AD), discovering that simple loss-of-function does not contribute to the inherited form of the neurodegenerative disorder.

The findings, published online in the journal Cell Reports, could help elucidate the still-mysterious mechanisms of Alzheimer’s disease and better inform development of effective drugs, said principal investigator Lawrence Goldstein, PhD, professor in the Departments of Cellular and Molecular Medicine and Neurosciences and director of the UC San Diego Stem Cell Program.

“In some ways, this is a powerful technical demonstration of the promise of stem cells and genomics research in better understanding and ultimately treating AD,” said Goldstein, who is also director of the new Sanford Stem Cell Clinical Center at UC San Diego. “We were able to identify and assign precise limits on how a mutation works in familial AD. That’s an important step in advancing the science, in finding drugs and treatments that can slow, maybe reverse, the disease’s devastating effects.”

Familial AD is a subset of early-onset Alzheimer’s disease that is caused by inherited gene mutations. Most cases of Alzheimer’s disease – there are an estimated 5.2 million Americans with AD – are sporadic and do not have a precise known cause, though age is a primary risk factor.   

More here

About

News from UC San Diego Health Sciences
Media Contacts: 619-543-6163
HealthSciComm@ucsd.edu

Blogroll

  • huffingtonpost
  • bbglasses
  • scientificillustration
  • comedycentral
  • kenobi-wan-obi
  • wnyc
  • latimes
  • scienceyoucanlove
  • awomaninscience
  • azspot
  • healthcareinfoguide
  • oupacademic
  • neurosciencestuff
  • kqedscience
  • mothernaturenetwork
  • fastcompany
  • madsweat
  • futureofscience
  • aspiringdoctors
  • mindblowingscience
  • tballardbrown
  • katiecouric
  • newyorker
  • scientificthought
  • molecularlifesciences
  • denverpost
  • boston
  • inothernews
  • medresearch
  • publicradiointernational
  • instagram
  • sdzoo
  • dystrophin
  • currentsinbiology
  • abcworldnews
  • buzzfeed
  • forum-network
  • theweekmagazine
  • therumpus
  • exploratorium
  • longform
  • rollingstone
  • newsweek
  • nprfreshair
  • pbstv
  • laboratoryequipment
  • npr
  • htdeverything
  • thevancouversun
  • nbcnightlynews
  • ari-abroad
  • statedept
  • theonion
  • mathcat345
  • think-progress
  • nbcnews
  • theatlantic
  • wayfaringmd
  • jtotheizzoe
  • alscientist
  • nursefocker
  • dodgemedlin
  • yahoonews
  • nprinterns
  • theskygazer
  • ucsdspecialcollections
  • pozmagazine
  • robotmuesli
  • prochoiceamerica
  • breakingnews
  • sdzsafaripark
  • explore-blog
  • officialssay
  • laweekly
  • journalofajournalist
  • onaissues
  • infographicjournal
  • pacificstand
  • prnewswire
  • usagov
  • ucsdmedialab
  • thisissandiego
  • usnews
  • wired
  • tmagazine
  • doctorswithoutborders
  • mashablehq
  • nydailynews
  • pulitzercenter
  • amnhnyc
  • thenewrepublic
  • queerability
  • nprglobalhealth
  • columbusdispatch
  • kateoplis
  • lakeconews
  • newswatchtv
  • surfnrunnr
  • peacecorps
  • nypl
  • pubhealth
  • plannedparenthood
  • sesamestreet
  • cenwatchglass
  • guardian
  • austinstatesman
  • sciencenetlinks
  • md-admissions
  • yaleuniversity
  • nursingmonkeymomma
  • medicalstate
  • soupsoup
  • colchrishadfield
  • actgnetwork
  • shortformblog
  • today
  • smithsonianmag
  • todaysdocument
  • medindia
  • seltzerlizard
  • post-mitotic
  • themedicalchronicles
  • breakingblog
  • sciencesoup
  • cancerninja
  • scinerds
  • ohscience
  • psydoctor8
  • thescienceofreality
  • huffpostscience
  • cnbc
  • psychotherapy
  • whitehouse
  • highcountrynews
  • scienceisbeauty
  • reuters
  • thisisfusion
  • newshour
  • photojojo
  • ucsdcancer
  • artandsciencejournal
  • msnbc
  • 3rdofmay
  • nprradiopictures
  • galindoyadira
  • markcoatney
  • skunkbear
  • thedailyshow
  • libertasacademica
  • cranquis
  • codeit
  • missmdisme
  • mediclopedia
  • robertreich
  • usatoday
  • bbsrc
  • natgeofound
  • staff
  • ucresearch
  • pritheworld
  • unicef
  • washingtonexaminer
  • michiganengineering
  • neurolove
  • bostongyrig
  • csmonitor
  • motherjones
  • ottawahealth
  • minnpost
  • doublejack
  • ucsdcrossculturalcenter
  • shortyawards
  • wnycradiolab
  • science-and-logic
  • medicalschool
  • pbsthisdayinhistory
  • hospitalreina
  • sciencechicks
  • americanpublicmedia
  • brookhavenlab
  • discoverynews
  • ziyadnazem
  • scipak
  • nocturnalnurse
  • nysci
  • tedx
  • nurse-on-duty
  • sciencenote
  • jayparkinsonmd
  • ladyjournos
  • poptech
  • ucsdcareerservicescenter
  • mediamed
  • brainmtters
  • aarp
  • neuroanatomyblog
  • fyeahmedlab
  • nprontheroad
  • articulomortis
  • science
  • poynterinstitute
  • timelightbox
  • artpoweratucsd
  • timemagazine
  • matthewkeys
  • paraphyletic
  • upworthyinsider
  • ucsd
  • topherchris
  • oh4theloveofscience
  • fuckyeahneuroscience
  • pneupnurse
  • utnereader
  • biocanvas
  • joshherigon
  • fuckyeahcardiovascularsystem
  • bitesizedbiology
  • bobedwardsradio
  • medethicslady
  • phdr
  • picturedept
  • fuckyeahnervoussystem
  • sci-fact
  • nationalpost
  • goodideapublichealth
  • carlzimmer
  • vetstail
  • chronicleofhighered
  • wgbhnews
  • ruled-by-secrecy
  • anaofta
  • tumblmd
  • life
  • dailymedical
  • oceanportal
  • ahfspeakout
  • captain-nitrogen
  • lookslikescience
  • genannetics
  • clearscience
  • thecoloradopursuit
  • artneuroscience
  • auditoryinsomniac
  • blamoscience
  • scishow
  • bio-sustain
  • information101
  • sciencephotolibrary
  • rubylipstick1
  • itsjustcharli
  • stemcellculture
  • houseofmind
  • scotthensley
  • a-science-blog
  • cheatsheet
  • bklynmed
  • bartholomewfromthesun
  • salon
  • wellcomebrains
  • aljazeera
  • globeandmail
  • kpcc
  • princeton-medbloro
  • blue-lights-and-tea
  • geneticist
  • couturecourier
  • reportingonhealth
  • ucsfbioengineering
  • coolhealthinfographics
  • thedailywhat
  • villagevoice
  • nbclatino
  • y2ycenter
  • ajebsary
  • realcleverscience
  • ohyeahdevelopmentalbiology
  • guardiancomment
  • timesopinion
  • scientificbritain
  • lifescienceexperiment
  • adschu
  • drwhitehall
  • poptechlabs
  • tokenladyscientist
  • washingtonpostinnovations
  • mountainlake
  • everythingmedical101
  • sdcms
  • mpbntech
  • kusp
  • natgeo