Dramatic Growth of Grafted Stem Cells in Rat Spinal Cord InjuriesReprogrammed human neurons extend axons almost entire length of central nervous system
Building upon previous research, scientists at the University of California, San Diego School of Medicine and Veteran’s Affairs San Diego Healthcare System report that neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals’ central nervous system.
Writing in the August 7 early online edition of Neuron, lead scientist Paul Lu, PhD, of the UC San Diego Department of Neurosciences and colleagues said the human iPSC-derived axons extended through the white matter of the injury sites, frequently penetrating adjacent gray matter to form synapses with rat neurons. Similarly, rat motor axons pierced the human iPSC grafts to form their own synapses. 
The iPSCs used were developed from a healthy 86-year-old human male.
“These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells,” said senior author Mark Tuszynski, MD, PhD, professor of Neurosciences and director of the UC San Diego Center for Neural Repair.
For several years, Tuszynski and colleagues have been steadily chipping away at the notion that a spinal cord injury necessarily results in permanent dysfunction and paralysis. Earlier work has shown that grafted stem cells reprogrammed to become neurons can, in fact, form new, functional circuits across an injury site, with the treated animals experiencing some restored ability to move affected limbs. The new findings underscore the potential of iPSC-based therapy and suggest a host of new studies and questions to be asked, such as whether axons can be guided and how will they develop, function and mature over longer periods of time.
While neural stem cell therapies are already advancing to clinical trials, this research raises cautionary notes about moving to human therapy too quickly, said Tuszynski.
“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible harmful side effects if axons are mistargeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame – months to years – or more rapidly. If maturity is reached on a human time frame, it could take months to years to observe functional benefits or problems in human clinical trials.”
In the latest work, Lu, Tuszynski and colleagues converted skin cells from a healthy 86-year-old man into iPSCs, which possess the ability to become almost any kind of cell. The iPSCs were then reprogrammed to become neurons in collaboration with the laboratory of Larry Goldstein, PhD, director of the UC San Diego Sanford Stem Cell Clinical Center. The new human neurons were subsequently embedded in a matrix containing growth factors and grafted into two-week-old spinal cord injuries in rats.
Three months later, researchers examined the post-transplantation injury sites. They found biomarkers indicating the presence of mature neurons and extensive axonal growth across long distances in the rats’ spinal cords, even extending into the brain. The axons traversed wound tissues to penetrate and connect with existing rat neurons. Similarly, rat neurons extended axons into the grafted material and cells. The transplants produced no detectable tumors.
While numerous connections were formed between the implanted human cells and rat cells, functional recovery was not found. However, Lu noted that tests assessed the rats’ skilled use of the hand. Simpler assays of leg movement could still show benefit. Also, several iPSC grafts contained scars that may have blocked beneficial effects of new connections. Continuing research seeks to optimize transplantation methods to eliminate scar formation.
Tuszynski said he and his team are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types.
“Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It’s easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”
Pictured: Image depicts extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury and transplantation of human induced pluripotent stem cell-derived neurons. Green fluorescent protein identifies human graft-derived axons, myelin (red) indicates host rat spinal cord white matter and blue marks host rat gray matter.

Dramatic Growth of Grafted Stem Cells in Rat Spinal Cord Injuries
Reprogrammed human neurons extend axons almost entire length of central nervous system

Building upon previous research, scientists at the University of California, San Diego School of Medicine and Veteran’s Affairs San Diego Healthcare System report that neurons derived from human induced pluripotent stem cells (iPSC) and grafted into rats after a spinal cord injury produced cells with tens of thousands of axons extending virtually the entire length of the animals’ central nervous system.

Writing in the August 7 early online edition of Neuron, lead scientist Paul Lu, PhD, of the UC San Diego Department of Neurosciences and colleagues said the human iPSC-derived axons extended through the white matter of the injury sites, frequently penetrating adjacent gray matter to form synapses with rat neurons. Similarly, rat motor axons pierced the human iPSC grafts to form their own synapses. 

The iPSCs used were developed from a healthy 86-year-old human male.

“These findings indicate that intrinsic neuronal mechanisms readily overcome the barriers created by a spinal cord injury to extend many axons over very long distances, and that these capabilities persist even in neurons reprogrammed from very aged human cells,” said senior author Mark Tuszynski, MD, PhD, professor of Neurosciences and director of the UC San Diego Center for Neural Repair.

For several years, Tuszynski and colleagues have been steadily chipping away at the notion that a spinal cord injury necessarily results in permanent dysfunction and paralysis. Earlier work has shown that grafted stem cells reprogrammed to become neurons can, in fact, form new, functional circuits across an injury site, with the treated animals experiencing some restored ability to move affected limbs. The new findings underscore the potential of iPSC-based therapy and suggest a host of new studies and questions to be asked, such as whether axons can be guided and how will they develop, function and mature over longer periods of time.

While neural stem cell therapies are already advancing to clinical trials, this research raises cautionary notes about moving to human therapy too quickly, said Tuszynski.

“The enormous outgrowth of axons to many regions of the spinal cord and even deeply into the brain raises questions of possible harmful side effects if axons are mistargeted. We also need to learn if the new connections formed by axons are stable over time, and if implanted human neural stem cells are maturing on a human time frame – months to years – or more rapidly. If maturity is reached on a human time frame, it could take months to years to observe functional benefits or problems in human clinical trials.”

In the latest work, Lu, Tuszynski and colleagues converted skin cells from a healthy 86-year-old man into iPSCs, which possess the ability to become almost any kind of cell. The iPSCs were then reprogrammed to become neurons in collaboration with the laboratory of Larry Goldstein, PhD, director of the UC San Diego Sanford Stem Cell Clinical Center. The new human neurons were subsequently embedded in a matrix containing growth factors and grafted into two-week-old spinal cord injuries in rats.

Three months later, researchers examined the post-transplantation injury sites. They found biomarkers indicating the presence of mature neurons and extensive axonal growth across long distances in the rats’ spinal cords, even extending into the brain. The axons traversed wound tissues to penetrate and connect with existing rat neurons. Similarly, rat neurons extended axons into the grafted material and cells. The transplants produced no detectable tumors.

While numerous connections were formed between the implanted human cells and rat cells, functional recovery was not found. However, Lu noted that tests assessed the rats’ skilled use of the hand. Simpler assays of leg movement could still show benefit. Also, several iPSC grafts contained scars that may have blocked beneficial effects of new connections. Continuing research seeks to optimize transplantation methods to eliminate scar formation.

Tuszynski said he and his team are attempting to identify the most promising neural stem cell type for repairing spinal cord injuries. They are testing iPSCs, embryonic stem cell-derived cells and other stem cell types.

“Ninety-five percent of human clinical trials fail. We are trying to do as much as we possibly can to identify the best way of translating neural stem cell therapies for spinal cord injury to patients. It’s easy to forge ahead with incomplete information, but the risk of doing so is greater likelihood of another failed clinical trial. We want to determine as best we can the optimal cell type and best method for human translation so that we can move ahead rationally and, with some luck, successfully.”

Pictured: Image depicts extension of human axons into host adult rat white matter and gray matter three months after spinal cord injury and transplantation of human induced pluripotent stem cell-derived neurons. Green fluorescent protein identifies human graft-derived axons, myelin (red) indicates host rat spinal cord white matter and blue marks host rat gray matter.

Birthday Matters for Wiring-Up the Brain’s Vision Centers
Researchers at the University of California, San Diego School of Medicine have evidence suggesting that neurons in the developing brains of mice are guided by a simple but elegant birth order rule that allows them to find and form their proper connections.
The study is published online July 31 in Cell Reports.
“Nothing about brain wiring is haphazard,” said senior author Andrew Huberman, PhD, assistant professor in the Department of Neurosciences, Division of Biological Sciences and Department of Ophthalmology, UC San Diego.
A mature, healthy brain has billions of precisely interconnected neurons. Yet the brain starts with just one neuron that divides and divides – up to 250,000 new neurons per minute at times during early development. The question for biologists has been how do these neurons decide which other neurons to connect to, a process neuroscientists call target selection.
The answer has both fundamental scientific value and clinical relevance. Some researchers believe that autism and other disorders linked to brain development may be caused, in part, by a failure of neurons to properly reposition their axons as needed when mistakes in target selection occur.
To better understand how a young brain gets wired, researchers focused on the development of retinal ganglion cells (RGCs) in mice. These cells connect the eyes and brain. Specifically, the main cell bodies of RGCs reside in the retina but their axons – slender projections along which electrical impulses travel – extend into the centers of the brain that process visual information and give rise to what we commonly think of as “sight,” as well as other light-influenced physiological processes, such as the effect of light on mood.
For the study, scientists tagged RGCs and watched where they directed their axons during development. The experiments revealed that specific types of RGCs target specific areas of the brain, allowing mice to do things such as sense direction of motion, move their eyes and detect changes in daily light cycles. It was also observed that some types of RGCs (such as those that detect brightness and control pupil constriction) are created early in development while others (such as those controlling eye movements) are created later.
The study’s main finding is that early RGCs (those created early in the sequence of brain division) make a lot of connections to other neurons and a lot of mistakes, which they then correct by repositioning or removing their axons. By contrast, later RGCs were observed to be highly accurate in their target selection skills and made almost no errors.
“The neurons are paying attention to when they were born and reading out which choices they should make based on their birthdate,” said Jessica Osterhout, a doctoral student in biology and the study’s lead author. “It seems to all boil down to birthdate.”
The idea that timing is important for cell differentiation is a classic principle of developmental biology, but this study is among the first to show that the timing of neuronal generation is linked to how neurons achieve specific brain wiring.
In addition to clarifying normal brain development, researchers plan to examine the role of time-dependent wiring mishaps in models of human disorders, such as autism and schizophrenia, as well as diseases specific to the visual system, such as congenital blindness.
“We want to know if in diseases such as autism neurons are made out of order and as a result get confused about which connections to make,” Huberman said.

Birthday Matters for Wiring-Up the Brain’s Vision Centers

Researchers at the University of California, San Diego School of Medicine have evidence suggesting that neurons in the developing brains of mice are guided by a simple but elegant birth order rule that allows them to find and form their proper connections.

The study is published online July 31 in Cell Reports.

“Nothing about brain wiring is haphazard,” said senior author Andrew Huberman, PhD, assistant professor in the Department of Neurosciences, Division of Biological Sciences and Department of Ophthalmology, UC San Diego.

A mature, healthy brain has billions of precisely interconnected neurons. Yet the brain starts with just one neuron that divides and divides – up to 250,000 new neurons per minute at times during early development. The question for biologists has been how do these neurons decide which other neurons to connect to, a process neuroscientists call target selection.

The answer has both fundamental scientific value and clinical relevance. Some researchers believe that autism and other disorders linked to brain development may be caused, in part, by a failure of neurons to properly reposition their axons as needed when mistakes in target selection occur.

To better understand how a young brain gets wired, researchers focused on the development of retinal ganglion cells (RGCs) in mice. These cells connect the eyes and brain. Specifically, the main cell bodies of RGCs reside in the retina but their axons – slender projections along which electrical impulses travel – extend into the centers of the brain that process visual information and give rise to what we commonly think of as “sight,” as well as other light-influenced physiological processes, such as the effect of light on mood.

For the study, scientists tagged RGCs and watched where they directed their axons during development. The experiments revealed that specific types of RGCs target specific areas of the brain, allowing mice to do things such as sense direction of motion, move their eyes and detect changes in daily light cycles. It was also observed that some types of RGCs (such as those that detect brightness and control pupil constriction) are created early in development while others (such as those controlling eye movements) are created later.

The study’s main finding is that early RGCs (those created early in the sequence of brain division) make a lot of connections to other neurons and a lot of mistakes, which they then correct by repositioning or removing their axons. By contrast, later RGCs were observed to be highly accurate in their target selection skills and made almost no errors.

“The neurons are paying attention to when they were born and reading out which choices they should make based on their birthdate,” said Jessica Osterhout, a doctoral student in biology and the study’s lead author. “It seems to all boil down to birthdate.”

The idea that timing is important for cell differentiation is a classic principle of developmental biology, but this study is among the first to show that the timing of neuronal generation is linked to how neurons achieve specific brain wiring.

In addition to clarifying normal brain development, researchers plan to examine the role of time-dependent wiring mishaps in models of human disorders, such as autism and schizophrenia, as well as diseases specific to the visual system, such as congenital blindness.

“We want to know if in diseases such as autism neurons are made out of order and as a result get confused about which connections to make,” Huberman said.

How Our Brains Store Recent Memories, Cell by Single CellFindings may shed light on how to treat neurological conditions like Alzheimer’s and epilepsy
Confirming what neurocomputational theorists have long suspected, researchers at the Dignity Health Barrow Neurological Institute in Phoenix, Ariz. and University of California, San Diego School of Medicine report that the human brain locks down episodic memories in the hippocampus, committing each recollection to a distinct, distributed fraction of individual cells.
The findings, published in the June 16 Early Edition of PNAS, further illuminate the neural basis of human memory and may, ultimately, shed light on new treatments for diseases and conditions that adversely affect it, such as Alzheimer’s disease and epilepsy.
“To really understand how the brain represents memory, we must understand how memory is represented by the fundamental computational units of the brain – single neurons – and their networks,” said Peter N. Steinmetz, MD, PhD, program director of neuroengineering at Barrow and senior author of the study. “Knowing the mechanism of memory storage and retrieval is a critical step in understanding how to better treat the dementing illnesses affecting our growing elderly population.”
Steinmetz, with first author John T. Wixted, PhD, Distinguished Professor of Psychology, Larry R. Squire, PhD, professor in the departments of neurosciences, psychiatry and psychology, both at UC San Diego, and colleagues, assessed nine patients with epilepsy whose brains had been implanted with electrodes to monitor seizures. The monitoring recorded activity at the level of single neurons.
The patients memorized a list of words on a computer screen, then viewed a second, longer list that contained those words and others. They were asked to identify words they had seen earlier, and to indicate how well they remembered them. The observed difference in the cell-firing activity between words seen on the first list and those not on the list clearly indicated that cells in the hippocampus were representing the patients’ memories of the words.
The researchers found that recently viewed words were stored in a distributed fashion throughout the hippocampus, with a small fraction of cells, about 2 percent, responding to any one word and a small fraction of words, about 3 percent, producing a strong change in firing in these cells.
"Intuitively, one might expect to find that any neuron that responds to one item from the list would also respond to the other items from the list, but our results did not look anything like that. The amazing thing about these counterintuitive findings is that they could not be more in line with what influential neurocomputational theorists long ago predicted must be true," said Wixted.
Although only a small fraction of cells coded recent memory for any one word, the scientists said the absolute number of cells coding memory for each word was large nonetheless – on the order of hundreds of thousands at least. Thus, the loss of any one cell, they noted, would have a negligible impact on a person’s ability to remember specific words recently seen.
Ultimately, the scientists said their goal is to fully understand how the human brain forms and represents memories of places and things in everyday life, which cells are involved and how those cells are affected by illness and disease. The researchers will next attempt to determine whether similar coding is involved in memories of pictures of people and landmarks and how hippocampal cells representing memory are impacted in patients with more severe forms of epilepsy.
Pictured: Human neuron showing actin formation in response to stimulation. Michael A. Colicos, UC San Diego

How Our Brains Store Recent Memories, Cell by Single Cell
Findings may shed light on how to treat neurological conditions like Alzheimer’s and epilepsy

Confirming what neurocomputational theorists have long suspected, researchers at the Dignity Health Barrow Neurological Institute in Phoenix, Ariz. and University of California, San Diego School of Medicine report that the human brain locks down episodic memories in the hippocampus, committing each recollection to a distinct, distributed fraction of individual cells.

The findings, published in the June 16 Early Edition of PNAS, further illuminate the neural basis of human memory and may, ultimately, shed light on new treatments for diseases and conditions that adversely affect it, such as Alzheimer’s disease and epilepsy.

“To really understand how the brain represents memory, we must understand how memory is represented by the fundamental computational units of the brain – single neurons – and their networks,” said Peter N. Steinmetz, MD, PhD, program director of neuroengineering at Barrow and senior author of the study. “Knowing the mechanism of memory storage and retrieval is a critical step in understanding how to better treat the dementing illnesses affecting our growing elderly population.”

Steinmetz, with first author John T. Wixted, PhD, Distinguished Professor of Psychology, Larry R. Squire, PhD, professor in the departments of neurosciences, psychiatry and psychology, both at UC San Diego, and colleagues, assessed nine patients with epilepsy whose brains had been implanted with electrodes to monitor seizures. The monitoring recorded activity at the level of single neurons.

The patients memorized a list of words on a computer screen, then viewed a second, longer list that contained those words and others. They were asked to identify words they had seen earlier, and to indicate how well they remembered them. The observed difference in the cell-firing activity between words seen on the first list and those not on the list clearly indicated that cells in the hippocampus were representing the patients’ memories of the words.

The researchers found that recently viewed words were stored in a distributed fashion throughout the hippocampus, with a small fraction of cells, about 2 percent, responding to any one word and a small fraction of words, about 3 percent, producing a strong change in firing in these cells.

"Intuitively, one might expect to find that any neuron that responds to one item from the list would also respond to the other items from the list, but our results did not look anything like that. The amazing thing about these counterintuitive findings is that they could not be more in line with what influential neurocomputational theorists long ago predicted must be true," said Wixted.

Although only a small fraction of cells coded recent memory for any one word, the scientists said the absolute number of cells coding memory for each word was large nonetheless – on the order of hundreds of thousands at least. Thus, the loss of any one cell, they noted, would have a negligible impact on a person’s ability to remember specific words recently seen.

Ultimately, the scientists said their goal is to fully understand how the human brain forms and represents memories of places and things in everyday life, which cells are involved and how those cells are affected by illness and disease. The researchers will next attempt to determine whether similar coding is involved in memories of pictures of people and landmarks and how hippocampal cells representing memory are impacted in patients with more severe forms of epilepsy.

Pictured: Human neuron showing actin formation in response to stimulation. Michael A. Colicos, UC San Diego

How to Erase a Memory – And Restore It
Researchers at the University of California, San Diego School of Medicine have erased and reactivated memories in rats, profoundly altering the animals’ reaction to past events.
The study, published in the June 1 advanced online issue of the journal Nature, is the first to show the ability to selectively remove a memory and predictably reactivate it by stimulating nerves in the brain at frequencies that are known to weaken and strengthen the connections between nerve cells, called synapses.
“We can form a memory, erase that memory and we can reactivate it, at will, by applying a stimulus that selectively strengthens or weakens synaptic connections,” said Roberto Malinow, MD, PhD, professor of neurosciences and senior author of the study.
Scientists optically stimulated a group of nerves in a rat’s brain that had been genetically modified to make them sensitive to light, and simultaneously delivered an electrical shock to the animal’s foot. The rats soon learned to associate the optical nerve stimulation with pain and displayed fear behaviors when these nerves were stimulated.
Analyses showed chemical changes within the optically stimulated nerve synapses, indicative of synaptic strengthening.
In the next stage of the experiment, the research team demonstrated the ability to weaken this circuitry by stimulating the same nerves with a memory-erasing, low-frequency train of optical pulses. These rats subsequently no longer responded to the original nerve stimulation with fear, suggesting the pain-association memory had been erased.
In what may be the study’s most startlingly discovery, scientists found they could re-activate the lost memory by re-stimulating the same nerves with a memory-forming, high-frequency train of optical pulses. These re-conditioned rats once again responded to the original stimulation with fear, even though they had not had their feet re-shocked.
“We can cause an animal to have fear and then not have fear and then to have fear again by stimulating the nerves at frequencies that strengthen or weaken the synapses,” said Sadegh Nabavi, a postdoctoral researcher in the Malinow lab and the study’s lead author.
In terms of potential clinical applications, Malinow, who holds the Shiley Endowed Chair in Alzheimer’s Disease Research in Honor of Dr. Leon Thal, noted that the beta amyloid peptide that accumulates in the brains of people with Alzheimer’s disease weakens synaptic connections in much the same way that low-frequency stimulation erased memories in the rats. “Since our work shows we can reverse the processes that weaken synapses, we could potentially counteract some of the beta amyloid’s effects in Alzheimer’s patients,” he said.

How to Erase a Memory – And Restore It

Researchers at the University of California, San Diego School of Medicine have erased and reactivated memories in rats, profoundly altering the animals’ reaction to past events.

The study, published in the June 1 advanced online issue of the journal Nature, is the first to show the ability to selectively remove a memory and predictably reactivate it by stimulating nerves in the brain at frequencies that are known to weaken and strengthen the connections between nerve cells, called synapses.

“We can form a memory, erase that memory and we can reactivate it, at will, by applying a stimulus that selectively strengthens or weakens synaptic connections,” said Roberto Malinow, MD, PhD, professor of neurosciences and senior author of the study.

Scientists optically stimulated a group of nerves in a rat’s brain that had been genetically modified to make them sensitive to light, and simultaneously delivered an electrical shock to the animal’s foot. The rats soon learned to associate the optical nerve stimulation with pain and displayed fear behaviors when these nerves were stimulated.

Analyses showed chemical changes within the optically stimulated nerve synapses, indicative of synaptic strengthening.

In the next stage of the experiment, the research team demonstrated the ability to weaken this circuitry by stimulating the same nerves with a memory-erasing, low-frequency train of optical pulses. These rats subsequently no longer responded to the original nerve stimulation with fear, suggesting the pain-association memory had been erased.

In what may be the study’s most startlingly discovery, scientists found they could re-activate the lost memory by re-stimulating the same nerves with a memory-forming, high-frequency train of optical pulses. These re-conditioned rats once again responded to the original stimulation with fear, even though they had not had their feet re-shocked.

“We can cause an animal to have fear and then not have fear and then to have fear again by stimulating the nerves at frequencies that strengthen or weaken the synapses,” said Sadegh Nabavi, a postdoctoral researcher in the Malinow lab and the study’s lead author.

In terms of potential clinical applications, Malinow, who holds the Shiley Endowed Chair in Alzheimer’s Disease Research in Honor of Dr. Leon Thal, noted that the beta amyloid peptide that accumulates in the brains of people with Alzheimer’s disease weakens synaptic connections in much the same way that low-frequency stimulation erased memories in the rats. “Since our work shows we can reverse the processes that weaken synapses, we could potentially counteract some of the beta amyloid’s effects in Alzheimer’s patients,” he said.

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.

Spheres of influence
Specific language impairment (SLI) is something of a misnomer. It’s a condition in which a person, typically first identified as a child, has difficulty speaking or communicating normally, but without obvious cause. Their hearing and general health are fine. There are no environmental or rearing experiences to explain it. There are no other signs of developmental delay or neurological disorder.
SLI seems hardly specific at all. And it’s the most common of childhood language disorders, affecting 7 percent of children.
“The primary requirements for the diagnosis are the failure to master spoken and written language expression and comprehension despite normal nonverbal intelligence and no sensory or other physical or medical condition that could cause it,” said Tim Brown, PhD, a developmental cognitive neuroscientist in the UC San Diego School of Medicine’s Department of Neurosciences and the UC San Diego Center for Human Development.
“Because it’s largely a diagnosis of exclusions, SLI likely has more than one cause and might be made up of different subtypes. Different kids with SLI can have very different profiles of language strengths and weaknesses.”
Although there are standard clinical treatments for speech production disorders, said Brown, there is no universally accepted treatment for SLI, in part because the problem is believed to involve non-motor “high-level” aspects of language.
In a recent paper published in the journal Frontiers in Human Neuroscience, Brown, Julia L. Evans, PhD, of the Center for Research in Language at UC San Diego and the School of Behavioral and Brain Sciences at the University of Texas, Dallas, and colleagues, describe using a technology called anatomically constrained magnetoencephalography imaging to look for “higher-level” aspects of language in a young SLI patient without requiring him to make speech movements or process auditory input.
They discovered that the adolescent boy’s brain represented objects in the opposite side of the brain than most people. “When he thinks about common objects, like a mouse, house, door, leaf or whale, and processes them vividly (like imagining their size), he uses his right brain hemisphere whereas most people rely most strongly on their left, which is thought to be the language processing hemisphere,” said Brown.
“This was true whether he was reading printed words of the objects or viewing pictures of them. With aMEG, we were able to show the specific regions of his brain that were used, with timing accurate down to the millisecond, which has not been seen before in SLI.”
Brown said the combination of spatial and temporal resolution gained using aMEG make it a promising method for better understanding what’s happening inside the brains of individual SLI patients. He said such precision may improve diagnoses and treatment.
“For example, although all children with SLI have language impairment, it may turn out that only a subset with SLI relies heavily on their right hemisphere for the cognitive processing of objects. Because of this difference in their brain’s functional organization, we might expect different cognitive or behavioral therapies to be effective for right hemisphere object processors versus left hemisphere processors. So the information about the individual child may be useful for both a better understanding of their problem and for leading them to a more appropriate treatment.”

Spheres of influence

Specific language impairment (SLI) is something of a misnomer. It’s a condition in which a person, typically first identified as a child, has difficulty speaking or communicating normally, but without obvious cause. Their hearing and general health are fine. There are no environmental or rearing experiences to explain it. There are no other signs of developmental delay or neurological disorder.

SLI seems hardly specific at all. And it’s the most common of childhood language disorders, affecting 7 percent of children.

“The primary requirements for the diagnosis are the failure to master spoken and written language expression and comprehension despite normal nonverbal intelligence and no sensory or other physical or medical condition that could cause it,” said Tim Brown, PhD, a developmental cognitive neuroscientist in the UC San Diego School of Medicine’s Department of Neurosciences and the UC San Diego Center for Human Development.

“Because it’s largely a diagnosis of exclusions, SLI likely has more than one cause and might be made up of different subtypes. Different kids with SLI can have very different profiles of language strengths and weaknesses.”

Although there are standard clinical treatments for speech production disorders, said Brown, there is no universally accepted treatment for SLI, in part because the problem is believed to involve non-motor “high-level” aspects of language.

In a recent paper published in the journal Frontiers in Human Neuroscience, Brown, Julia L. Evans, PhD, of the Center for Research in Language at UC San Diego and the School of Behavioral and Brain Sciences at the University of Texas, Dallas, and colleagues, describe using a technology called anatomically constrained magnetoencephalography imaging to look for “higher-level” aspects of language in a young SLI patient without requiring him to make speech movements or process auditory input.

They discovered that the adolescent boy’s brain represented objects in the opposite side of the brain than most people. “When he thinks about common objects, like a mouse, house, door, leaf or whale, and processes them vividly (like imagining their size), he uses his right brain hemisphere whereas most people rely most strongly on their left, which is thought to be the language processing hemisphere,” said Brown.

“This was true whether he was reading printed words of the objects or viewing pictures of them. With aMEG, we were able to show the specific regions of his brain that were used, with timing accurate down to the millisecond, which has not been seen before in SLI.”

Brown said the combination of spatial and temporal resolution gained using aMEG make it a promising method for better understanding what’s happening inside the brains of individual SLI patients. He said such precision may improve diagnoses and treatment.

“For example, although all children with SLI have language impairment, it may turn out that only a subset with SLI relies heavily on their right hemisphere for the cognitive processing of objects. Because of this difference in their brain’s functional organization, we might expect different cognitive or behavioral therapies to be effective for right hemisphere object processors versus left hemisphere processors. So the information about the individual child may be useful for both a better understanding of their problem and for leading them to a more appropriate treatment.”

Human neural progenitor cells isolated under selective culture conditions from the developing human brain and directed through lineage differentiation. Neural progenitor cells are stained green; differentiated astrocytes are orange. Nuclei are stained blue. Image courtesy of the National Institute of Neurological Disorders and Stroke. 
Protein Switch Dictates Cellular Fate: Stem Cell or Neuron
Researchers at the University of California, San Diego School of Medicine have discovered that a well-known protein has a new function: It acts in a biological circuit to determine whether an immature neural cell remains in a stem-like state or proceeds to become a functional neuron.
The findings, published in the February 13 online issue of Cell Reports, more fully illuminate a fundamental but still poorly understood cellular act – and may have significant implications for future development of new therapies for specific neurological disorders, including autism and schizophrenia.
Postdoctoral fellow Chih-Hong Lou, working with principal investigator Miles F. Wilkinson, PhD, professor in the Department of Reproductive Medicine and a member of the UC San Diego Institute for Genomic Medicine, and other colleagues, discovered that this critical biological decision is controlled by UPF1, a protein essential for the nonsense-mediated RNA decay (NMD) pathway.
NMD was previously established to have two broad roles. First, it is a quality control mechanism used by cells to eliminate faulty messenger RNA (mRNA) – molecules that help transcribe genetic information into the construction of proteins essential to life.  Second, it degrades a specific group of normal mRNAs.  The latter function of NMD has been hypothesized to be physiologically important, but until now it had not been clear whether this is the case.
Wilkinson and colleagues discovered that in concert with a special class of RNAs called microRNA, UPF1 acts as a molecular switch to determine when immature (non-functional) neural cells differentiate into non-dividing (functional) neurons. Specifically, UPF1 triggers the decay of a particular mRNA that encodes for a protein in the TGF-? signaling pathway that promotes neural differentiation.  By degrading that mRNA, the encoded protein fails to be produced and neural differentiation is prevented.  Thus, Lou and colleagues identified for the first time a molecular circuit in which NMD acts to drive a normal biological response.
NMD also promotes the decay of mRNAs encoding proliferation inhibitors, which Wilkinson said may explain why NMD stimulates the proliferative state characteristic of stem cells. 
“There are many potential clinical ramifications for these findings,” Wilkinson said. “One is that by promoting the stem-like state, NMD may be useful for reprogramming differentiated cells into stem cells more efficiently. 
“Another implication follows from the finding that NMD is vital to the normal development of the brain in diverse species, including humans.  Humans with deficiencies in NMD have intellectual disability and often also have schizophrenia and autism. Therapies to enhance NMD in affected individuals could be useful in restoring the correct balance of stem cells and differentiated neurons and thereby help restore normal brain function.”

Human neural progenitor cells isolated under selective culture conditions from the developing human brain and directed through lineage differentiation. Neural progenitor cells are stained green; differentiated astrocytes are orange. Nuclei are stained blue. Image courtesy of the National Institute of Neurological Disorders and Stroke.

Protein Switch Dictates Cellular Fate: Stem Cell or Neuron

Researchers at the University of California, San Diego School of Medicine have discovered that a well-known protein has a new function: It acts in a biological circuit to determine whether an immature neural cell remains in a stem-like state or proceeds to become a functional neuron.

The findings, published in the February 13 online issue of Cell Reports, more fully illuminate a fundamental but still poorly understood cellular act – and may have significant implications for future development of new therapies for specific neurological disorders, including autism and schizophrenia.

Postdoctoral fellow Chih-Hong Lou, working with principal investigator Miles F. Wilkinson, PhD, professor in the Department of Reproductive Medicine and a member of the UC San Diego Institute for Genomic Medicine, and other colleagues, discovered that this critical biological decision is controlled by UPF1, a protein essential for the nonsense-mediated RNA decay (NMD) pathway.

NMD was previously established to have two broad roles. First, it is a quality control mechanism used by cells to eliminate faulty messenger RNA (mRNA) – molecules that help transcribe genetic information into the construction of proteins essential to life.  Second, it degrades a specific group of normal mRNAs.  The latter function of NMD has been hypothesized to be physiologically important, but until now it had not been clear whether this is the case.

Wilkinson and colleagues discovered that in concert with a special class of RNAs called microRNA, UPF1 acts as a molecular switch to determine when immature (non-functional) neural cells differentiate into non-dividing (functional) neurons. Specifically, UPF1 triggers the decay of a particular mRNA that encodes for a protein in the TGF-? signaling pathway that promotes neural differentiation.  By degrading that mRNA, the encoded protein fails to be produced and neural differentiation is prevented.  Thus, Lou and colleagues identified for the first time a molecular circuit in which NMD acts to drive a normal biological response.

NMD also promotes the decay of mRNAs encoding proliferation inhibitors, which Wilkinson said may explain why NMD stimulates the proliferative state characteristic of stem cells. 

“There are many potential clinical ramifications for these findings,” Wilkinson said. “One is that by promoting the stem-like state, NMD may be useful for reprogramming differentiated cells into stem cells more efficiently. 

“Another implication follows from the finding that NMD is vital to the normal development of the brain in diverse species, including humans.  Humans with deficiencies in NMD have intellectual disability and often also have schizophrenia and autism. Therapies to enhance NMD in affected individuals could be useful in restoring the correct balance of stem cells and differentiated neurons and thereby help restore normal brain function.”

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