Posts tagged ALS
Articles and news from the latest research reports.
(Image caption: In the top image, cells from a mouse model of amyotrophic lateral sclerosis caused normal healthy brain cells (green) to die. But when scientists blocked an enzyme in the cells from the mouse model, more of the normal cells and their branches survived (bottom))
Digoxin, a medication used in the treatment of heart failure, may be adaptable for the treatment of amyotrophic lateral sclerosis (ALS), a progressive, paralyzing disease, suggests new research at Washington University School of Medicine in St. Louis.
ALS, also known as Lou Gehrig’s disease, destroys the nerve cells that control muscles. This leads to loss of mobility, difficulty breathing and swallowing and eventually death. Riluzole, the sole medication approved to treat the disease, has only marginal benefits in patients.
But in a new study conducted in cell cultures and in mice, scientists showed that when they reduced the activity of an enzyme or limited cells’ ability to make copies of the enzyme, the disease’s destruction of nerve cells stopped. The enzyme maintains the proper balance of sodium and potassium in cells.
“We blocked the enzyme with digoxin,” said senior author Azad Bonni, MD, PhD. “This had a very strong effect, preventing the death of nerve cells that are normally killed in a cell culture model of ALS.”
The findings appear online Oct. 26 in Nature Neuroscience.
The results stemmed from Bonni’s studies of brain cells’ stress responses in a mouse model of ALS. The mice have a mutated version of a gene that causes an inherited form of the disease and develop many of the same symptoms seen in humans with ALS, including paralysis and death.
Efforts to monitor the activity of a stress response protein in the mice unexpectedly led the scientists to another protein: sodium-potassium ATPase. This enzyme ejects charged sodium particles from cells and takes in charged potassium particles, allowing cells to maintain an electrical charge across their outer membranes.
Maintenance of this charge is essential for the normal function of cells. The particular sodium-potassium ATPase highlighted by Bonni’s studies is found in nervous system cells called astrocytes. In the ALS mice, levels of the enzyme are higher than normal in astrocytes.
Bonni’s group found that the increase in sodium-potassium ATPase led the astrocytes to release harmful factors called inflammatory cytokines, which may kill motor neurons.
Recent studies have suggested that astrocytes may be crucial contributors to neurodegenerative disorders such as ALS, and Alzheimer’s, Huntington’s and Parkinson’s diseases. For example, placing astrocytes from ALS mice in culture dishes with healthy motor neurons causes the neurons to degenerate and die.
“Even though the neurons are normal, there’s something going on in the astrocytes that is harming the neurons,” said Bonni, the Edison Professor of Neurobiology and head of the Department of Anatomy and Neurobiology.
How this happens isn’t clear, but Bonni’s results suggest the sodium-potassium ATPase plays a key role. When he conducted the same experiment but blocked the enzyme in ALS astrocytes using digoxin, the normal motor nerve cells survived. Digoxin blocks the ability of sodium-potassium ATPase to eject sodium and bring in potassium.
In mice with the mutation for inherited ALS, those with only one copy of the gene for sodium-potassium ATPase survived an average of 20 days longer than those with two copies of the gene. When one copy of the gene is gone, cells make less of the enzyme.
“The mice with only one copy of the sodium-potassium ATPase gene live longer and are more mobile,” Bonni said. “They’re not normal, but they can walk around and have more motor neurons in their spinal cords.”
Many important questions remain about whether and how inhibitors of the sodium-potassium ATPase enzyme might be used to slow progressive paralysis in ALS, but Bonni said the findings offer an exciting starting point for further studies.
(Image caption: During development, nerve cells (shown in blue, green, violet and yellow) extend their axons to target leg muscles. If the EphA4 receptors of the growing nerve cells no longer encounter freely accessible ephrins, the axons of many nerve cells (violet) are no longer able to find their partner cells. Credit: © MPI of Neurobiology / Gatto)
Neurons in a forest of signposts
Our ability to move relies on the correct formation of connections between different nerve cells and between nerve and muscle cells. Growing axons of nerve cells are guided to their targets by signposts expressed on the surface of other cells. Very prominent are “do not enter” signs that push axons away. Cell culture studies suggest that protein-cutting enzymes (proteases) remove these signs as soon as they are recognized by the growing axons. In this way, the “bond of recognition” between the axon and the sign is quickly broken, and the axons are more easily guided in a new direction. Scientists from the Max Planck Institute of Neurobiology in Martinsried and the Institut de Recherches Cliniques de Montréal have now shown that proteases indeed control the navigation of growing axons. However, contrary to the current belief, they do so by regulating the number of existing signs. Without proteases, the signposts would be masked and the axons would grow in the wrong direction. These findings clarified how cells form connections during development and may also improve our understanding of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS).
The human brain consists of about 100 billion nerve cells. During embryonic development each of these cells connects with other cells by means of a long extension, known as axon. Some axons need to navigate long distances through the body to find their correct targets, for example from the spinal cord down to the foot. Only if all these connections are correctly established we can perform basic and fine-tuned movements, such as walking or playing the piano.
It is therefore essential that each nerve cell finds its correct target. But how does an axon navigate and find the appropriate partner cells among billions of other possible targets? “We have now identified a few dozen guidance molecules and their receptors that help axons orient themselves,” says Rüdiger Klein, Director at the Max Planck Institute of Neurobiology. “However, these few receptor-guidance molecule pairs need to control a very large number of navigational decisions. Therefore, there must be some mechanisms to amplify and modulate the effects of these protein pairs”.
Cutting for speed?
Over the last decade, Rüdiger Klein and his team have been studying how nerve cells find their way during development. They are focusing on “do not enter” signs, e.g. ephrin guidance molecules and their Eph receptors. Ephrins and Eph receptors, being present on almost all cell surfaces: on axons as well as on cells in the surrounding tissues, help the growing axons to explore their surroundings and locate their partner cells.
As an axon travels through the body, it docks again and again to other cells via the ephrin/Eph system. This triggers cellular processes, in one or both cells, that eventually cause the connection to be severed and the cells to repel each other, preventing the axon to grow in the wrong direction. It has been hypothesised that this cellular repulsion is accelerated by proteases. Proteases are enzymes that cut Eph receptors and/or ephrins, thus by severing the Eph/ephrin bond between two opposing cells they might expedite the repulsion process. “In this way, proteases could contribute to changes in the guidance process – but this has not yet been experimentally proven.” says Rüdiger Klein.
Not faster, but better
To address this question, the neurobiologists studied how proteases affect the rate of cellular repulsion controlled by EphA4 receptors and ephrins. “Although the experiments in cell culture initially appeared to confirm the theory, we discovered something quite different in living organisms,” states Rüdiger Klein. Contrary to expectations, cellular repulsion proceeded with undiminished accuracy in animals whose axons expressed EphA4 receptors resistant to protease severing. On the other hand, in animals whose axons and muscles expressed EphA4 receptors resistant to protease cutting many axons grew in the wrong direction. Because no cutting occurred, more and more functional EphA4 receptors accumulated on cell surfaces of the leg tissues. This accumulation caused EphA4 receptors to bind to the ephrins on the same cell surface, a phenomena termed as “masking”. Consequently, the ephrins could no longer act as “do not enter” signs for the growing axons. Thus, axons, being no longer repelled, are misguided in a “no entry zone” and are unable to find their correct targets.
These results show that the cleavage of Eph receptors by proteases does not, as expected, accelerate the repulsion reaction. Instead, it regulates the number of functioning receptors and indirectly the number of available ephrins on cells, where they serve as navigational aids. If the balance is disrupted, growing axons are misdirected.
This is an important finding, as EphA4 receptors perform essential functions during the development of neural networks in the brain and in the spinal cord. They are also involved in neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). In the absence of EphA4 receptors, ALS manifests itself later and develops more slowly in a number of animal models. “It’s possible that the number of EphA4 receptors is kept low by the regulatory activity of proteases,” Rüdiger Klein reflects. “This could provide a way to exert a positive influence on the course of ALS.”
Scientists Link ALS Progression to Increased Protein Instability
A new study by scientists from The Scripps Research Institute (TSRI), Lawrence Berkeley National Laboratory (Berkeley Lab) and other institutions suggests a cause of amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease.
“Our work supports a common theme whereby loss of protein stability leads to disease,” said John A. Tainer, professor of structural biology at TSRI and senior scientist at Berkeley Lab, who shared senior authorship of the new research with TSRI Professor Elizabeth Getzoff.
Getzoff, Tainer and their colleagues, who focused on the effects of mutations to a gene coding for a protein called superoxide dismutase (SOD), report their findings this week in the online Early Edition of the Proceedings of the National Academy of Sciences. The study provides evidence that those proteins linked to more severe forms of the disease are less stable structurally and more prone to form clusters or aggregates.
“The suggestion here is that strategies for stabilizing SOD proteins could be useful in treating or preventing SOD-linked ALS,” said Getzoff.
Striking in the Prime of Life
ALS is notorious for its ability to strike down people in the prime of life. It first leapt into public consciousness when it afflicted baseball star Lou Gehrig, who succumbed to the disease in 1941 at the age of only 38. Recently, the ALS Association’s Ice Bucket Challenge has enhanced public awareness of the disease.
ALS kills by destroying muscle-controlling neurons, ultimately including those that control breathing. At any one time, about 10,000 Americans are living with the disease, according to new data from the Centers for Disease Control and Prevention, but it is almost always lethal within several years of the onset of symptoms.
SOD1 mutations, the most studied factors in ALS, are found in about a quarter of hereditary ALS cases and seven percent of ordinary “sporadic” ALS cases. SOD-linked ALS has nearly 200 variants, each associated with a distinct SOD1 mutation. Scientists still don’t agree, though, on just how the dozens of different SOD1 mutations all lead to the same disease.
One feature that SOD1-linked forms of ALS do have in common is the appearance of SOD clusters or aggregates in affected motor neurons and their support cells. Aggregates of SOD with other proteins are also found in affected cells, even in ALS cases that are not linked to SOD1 mutations.
In 2003, based on their and others’ studies of mutant SOD proteins, Tainer, Getzoff and their colleagues proposed the “framework destabilization” hypothesis. In this view, ALS-linked mutant SOD1 genes all code for structurally unstable forms of the SOD protein. Inevitably some of these unstable SOD proteins lose their normal folding enough to expose sticky elements that are normally kept hidden, and they begin to aggregate with one another, faster than neuronal cleanup systems can keep up—and that accumulating SOD aggregation somehow triggers disease.
Faster Clumping, Worse Disease
In the new study, the Tainer and Getzoff laboratories and their collaborators used advanced biophysical methods to probe how different SOD1 gene mutations in a particular genetic ALS “hotspot” affect SOD protein stability.
To start, they examined how the aggregation dynamics of the best-studied mutant form of SOD, known as SOD G93A, differed from that of non-mutant, “wild-type” SOD. To do this, they developed a method for gradually inducing SOD aggregation, which was measured with an innovative structural imaging system called SAXS (small-angle X-ray scattering) at Berkeley Lab’s SIBYLS beamline.
“We could detect differences between the two proteins even before we accelerated the aggregation process,” said David S. Shin, a research scientist in Tainer’s laboratories at Berkeley Lab and TSRI who continues structural work on SOD at Berkeley.
The G93A SOD aggregated more quickly than wild-type SOD, but more slowly than an SOD mutant called A4V that is associated with a more rapidly progressing form of ALS.
Subsequent experiments with G93A and five other G93 mutants (in which the amino acid glycine at position 93 on the protein is replaced with a different amino acid) revealed that the mutants formed long, rod-shaped aggregates, compared to the compact folded structure of wild-type SOD. The mutant SOD proteins that more quickly formed longer aggregates were again those that corresponded to more rapidly progressing forms of ALS.
What could explain these SOD mutants’ diminished stability? Further tests focused on the role of a copper ion that is normally incorporated within the SOD structure and helps stabilize the protein. Using two other techniques, electron-spin resonance (ESR) spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS), the researchers found that the G93-mutant SODs seemed normal in their ability to take up copper ions, but had a reduced ability to retain copper under mildly stressing conditions—and this ability was lower for the SOD mutants associated with more severe ALS.
“There were indications that the mutant SODs are more flexible than wild-type SOD, and we think that explains their relative inability to retain the copper ions,” said Ashley J. Pratt, the first author of the study, who was a student in the Getzoff laboratory and postdoctoral fellow with Tainer at Berkeley Lab.
Toward New Therapies
In short, the G93-mutant SODs appear to have looser, floppier structures that are more likely to drop their copper ions—and thus are more likely to misfold and stick together in aggregates.
Along with other researchers in the field, Getzoff and Tainer suspect that deviant interactions of mutant SOD trigger inflammation and disrupt ordinary protein trafficking and disposal systems, stressing and ultimately killing affected neurons.
“Because mutant SODs get bent out of shape more easily,” said Getzoff, “they don’t hold and release their protein partners properly. By defining these defective partnerships, we can provide new targets for the development of drugs to treat ALS.”
The researchers also plan to confirm the relationship between structural stability and ALS severity in other SOD mutants.
“If our hypothesis is correct,” said Shin, “future therapies to treat SOD-linked ALS need not be tailored to each individual mutation—they should be applicable to all of them.”
Scientists Develop First Animal Model for ALS Dementia
The first animal model for ALS dementia, a form of ALS that also damages the brain, has been developed by Northwestern Medicine scientists. The advance will allow researchers to directly see the brains of living mice, under anesthesia, at the microscopic level. This will allow direct monitoring of test drugs to determine if they work.
This is one of the latest research findings since the ALS Ice Bucket Challenge heightened interest in the disease and the need for expanded research and funding.
“This new model will allow rapid testing and direct monitoring of drugs in real time,” said Northwestern scientist and study senior author Teepu Siddique, MD. “This will allow scientists to move quickly and accelerate the testing of drug therapies.”
The new mouse model has the pathological hallmarks of the disease in humans with mutations in the genes for UBQLN2 (ubliqulin 2) and SQSTM1 (P62) that Siddique and colleagues identified in 2011. That pathology was linked to all forms of ALS and ALS/dementia.
Dr. Siddique and Han-Xiang Deng, MD, the corresponding authors on the paper, said they have reproduced behavioral, neurophysiological and pathological changes in a mouse that mimic this form of dementia associated with ALS (amyotrophic lateral sclerosis).
Dr. Siddique is the Les Turner ALS Foundation/Herbert C. Wenske Professor of Neurology at Northwestern University Feinberg School of Medicine and a neurologist at Northwestern Memorial Hospital. Dr. Deng is a research professor in Neurology at Feinberg.
The study was published Sept. 22 in the Proceedings of the National Academy of Sciences.
It’s been difficult for scientists to reproduce the genetic mutations of ALS, especially ALS/dementia in animal models, Dr. Siddique noted, which has hampered drug therapy testing.
Five percent or more of ALS cases, also known as Lou Gherig’s disease, also have ALS/dementia.
“ALS with dementia is an even more vicious disease than ALS alone because it attacks the brain causing changes in behavior and language well as causing paralysis,” Dr. Siddique said.
ALS affects an estimated 350,000 people worldwide, with an average survival of three years. In this progressive neurological disorder, the degeneration of neurons leads to muscle weakness and impaired speaking, swallowing and breathing, eventually causing paralysis and death. The associated dementia affects behavior and may affect decision-making, judgment, insight and language.
(Source: feinberg.northwestern.edu)
Mouse Model Sheds Light Mitochondria’s Role in Neurodegenerative Diseases
A new study by researchers at the University of Utah School of Medicine sheds light on a longstanding question about the role of mitochondria in debilitating and fatal motor neuron diseases and resulted in a new mouse model to study such illnesses.
Researchers led by Janet Shaw, Ph.D., professor of biochemistry, found that when healthy, functioning mitochondria was prevented from moving along axons – nerve fibers that conduct electricity away from neurons – mice developed symptoms of neurodegenerative diseases. In a study in the Proceedings of the National Academy of Sciences, Shaw and her research colleagues said their findings indicate that motor neuron diseases might result from poor distribution of mitochondria along the spinal cord and axons. First author Tammy T. Nguyen, is a student in the U medical school’s M.D./Ph.D. program, which aims to produce physicians with outstanding clinical skills and rigorous scientific training to bridge the worlds of clinical medicine and basic research to improve health care.
“We’ve known for a long time of the link between mitochondrial function and distribution and neural disease,” Shaw says. “But we haven’t been able to tell if the defect occurs because mitochondria aren’t getting to the right place or because they’re not functioning correctly.”
Mitochondria are organelles – compartments contained inside cells – that serve several functions, including making ATP, a nucleotide that cells convert into chemical energy to stay alive. For this reason mitochondria often are called “cellular power plants.” They also play a critical role in preventing too much calcium from building up in cells, which can cause apoptosis, or cell death.
For mitochondria to perform its functions, it must be distributed to cells throughout the body, which is accomplished with the help of small protein “motors” that transport the organelles along axons. For the motors to transport mitochondria, enzymes known as Mitochondrial Rho (Miro1) GTPases act to attach mitochondria to the motors. To study how the movement of mitochondria is related to motor neuron disease, Nguyen developed two mouse models in which the gene that makes Miro1 was knocked out. In one model, mice lacked Miro1 during the embryonic stage. A second model lacked the enzyme in the cerebral cortex, spinal cord and hippocampus.
The researchers observed that mice lacking Miro1 during the embryonic stage had motor neuron defects that prevented them from taking a single breath once born. After examining the mice, Nguyen, Shaw and their colleagues discovered that neurons required for breathing after birth were missing from the upper half of the mice’s brain stems. The phrenic nerve, also important for breathing, was not fully developed, either.
“We believe the physical difficulties in the mice indicated there were motor neuron defects,” Shaw says.
Conversely, the mice without Miro1 in their brain and spinal cord were fine at birth but soon developed signs of neurological problems, such as hunched spines, difficulty moving and clasping their hind paws together, and died around 35 days after birth. Those symptoms appeared similar to motor neuron disease, according to Shaw.
“The mitochondrial function in the cells appeared to be fine, and calcium levels were normal,” she says. “This shows for the first time that restricting mitochondrial movement and distribution could cause neuronal disease.”
Stefan M. Pulst, M.D., Dr. med, professor and chair of the University’s neurology department and a co-author on the study, says the mitochondrial transport process is important not just for motor neurons but other neurons as well. “The Miro1 proteins and the respective animal models represent a breakthrough for studying ALS (Lou Gehrig’s disease) and other neurodegenerative diseases.”
Although much more research must be done, the study opens the possibility of developing new drugs to partially correct the mitochondrial distribution defects to slow the progression of motor neuron diseases. First, Shaw wants to generate a model to knock out the Miro1 gene in adult mice to see if the results mimic neurological diseases.
Control your environment through brain commands
Many patients with amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s Disease) and other neurodegenerative conditions live every day with a frustrating inability to do small, everyday tasks, such as turning on the lights, changing the volume on the TV, or even communicating with their friends and loved ones.
Today, a first-ever proof of concept demonstrates how wearable technology and consumer products can be brought together with digital innovations to let a person with no mobility control their environment using brain commands, via a custom-built tablet application and wearable display interface.
This proof of concept demonstrates the potential to improve the quality of life for ALS patients – or any person with limited muscle and speech function – by giving them the ability to interact, communicate and issue commands without moving their body or using their voice.
Researchers develop strategy to combat genetic ALS, FTD
A team of researchers at Mayo Clinic and The Scripps Research Institute in Florida have developed a new therapeutic strategy to combat the most common genetic risk factor for the neurodegenerative disorders amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease) and frontotemporal dementia (FTD). In the Aug. 14 issue of Neuron, they also report discovery of a potential biomarker to track disease progression and the efficacy of therapies.
The scientists developed a small-molecule drug compound to prevent abnormal cellular processes caused by a mutation in the C9ORF72 gene. The findings come on the heels of previous discoveries by Mayo investigators that the C9ORF72 mutation produces an unusual repetitive genetic sequence that causes the buildup of abnormal RNA in brain cells and spinal cord.
While toxic protein clumps have long been implicated in neurodegeneration, this new strategy takes aim at abnormal RNA, which forms before toxic proteins in C9ORF72-related disorders (c9FTD/ALS). “Our study shows that toxic RNA produced in people with the c9FTD/ALS mutation is indeed a viable drug target,” says the study’s co-senior investigator, Leonard Petrucelli, Ph.D., a molecular neuroscientist at Mayo Clinic in Florida.
The compound, which was tested in cell culture models of c9FTD/ALS, bound to and blocked RNA’s ability to interact with other key proteins, thereby preventing the formation of toxic RNA clumps and “c9RAN proteins” that results from a process called repeat-associated non-ATG (RAN) translation.
The researchers also discovered that c9RAN proteins produced by the abnormal RNA can be measured in the spinal fluid of ALS patients. They are now evaluating whether these proteins are also present in spinal fluid of patients diagnosed with FTD. Although ALS primarily affects motor neurons leading to impaired mobility, speech, swallowing, and respiratory function and FTD affects brain regions that support higher cognitive function, some patients have symptoms of both disorders.
“Development of a readily accessible biomarker for the c9FTD/ALS mutation may aid not only diagnosis of these disorders and allow for tracking disease course in patients, but it could provide a more direct way to evaluate the response to experimental treatments,” says co-author Kevin Boylan, M.D., medical director of the Mayo Jacksonville ALS Center, the only ALS Certified Center of Excellence in Florida.
For example, a decrease in the levels of c9RAN proteins in response to treatment would suggest that a drug is having a desired effect. “The potential of this biomarker discovery is very exciting — even if we are in early days of development of such a test,” he says.
Since ALS is usually fatal two to five years after diagnosis and there is currently no effective treatment for FTD, these landmark findings offer the possibility of both improved diagnosis and treatment for up to 40 percent of all patients with familial (inherited) ALS and up to 25 percent of patients with familial FTD, says Dr. Boylan.
“One of the most exciting aspects of these studies has, in my opinion, been the seamless collaboration of our Florida biosciences institutes — Scripps and Mayo. Our collective biological and chemical expertise made this research possible,” says the other co-senior investigator, Mathew Disney, Ph.D., a professor of chemistry at Scripps Florida.
Dr. Disney and his group studied the structure of the RNA that resulted from the C9ORF72 mutation, and then designed the lead small-molecules. The Mayo team developed the patient-derived cell models to test the compounds in. Both teams then worked together to show that the lead agent’s mode of action was targeting the toxic RNA.
At last, hope for ALS patients?
U of T researchers have found a missing link that helps to explain how ALS, one of the world’s most feared diseases, paralyses and ultimately kills its victims. The breakthrough is helping them trace a path to a treatment or even a cure.
“ALS research has been taking baby steps for decades, but this has recently started changing to giant leaps,” said Karim Mekhail, professor in the Faculty of Medicine’s Department of Laboratory Medicine and Pathobiology. “The disease is linked to a large number of genes, and previously, every time someone studied one of them, it took them off in a different direction. Nobody could figure out how they were all connected.”
Mekhail and his team discovered the function of a crucial gene called PBP1 or ATAXIN2 that’s often missing in ALS, also known as Lou Gehrig’s Disease. Learning how this gene functions has helped them connect a lot of dots.
“This is an extremely important finding that may help us to better understand and target the pathways involved in neurodegenerative disease,” said Lorne Zinman, professor of medicine at U of T and medical director of the ALS/Neuromuscular Clinic at Sunnybrook Health Sciences Centre. “The next step will be to determine if this finding is applicable to patients with ALS.”
The key lies in a peculiarity of the human genome. It starts with the DNA, the blueprint that contains all our genetic information. The DNA passes its information to the RNA, which floats off to make proteins that help run our bodies. However, without ATAXIN2, the RNA fails to float away. It becomes glued to the DNA and forms RNA-DNA hybrids, said Mekhail. These hybrids gum up the works and stop other RNA from fully forming. Pieces of half-created RNA debris clutter the cell, and cause more hybrids.
“We think the debris and hybrids are on the same team in a never-ending Olympic relay race,” said Mekhail. “Over time there’s a vicious cycle building up. If we can find a way to disrupt that cycle, theoretically we can control or reverse the disease.”
On that front, Mekhail made a very surprising discovery: reducing calories to the minimum necessary amount stops the hybrids from forming in cells missing ATAXIN2. He and his team are studying whether a simple, non-toxic dietary restriction could be used with ALS patients, especially in the early stages or for those at risk of ALS.
Mekhail discovered the hybrids and missing genes in yeast cells and his results were published as the cover article for the July 28 edition of the journal Developmental Cell. Now his team is replicating this research on tissue from ALS patients – with very encouraging preliminary results.
“Within the next decade or two, I think there’s going to be a revolution in treatment for ALS and all kinds of brain disease,” he said. “These hybrids are going to play a role not just in ALS but in a lot of disease.”
(Source: media.utoronto.ca)
Could boosting brain cells’ appetites fight disease? New research shows promise
Deep inside the brains of people with dementia and Lou Gehrig’s disease, globs of abnormal protein gum up the inner workings of brain cells – dooming them to an early death.
But boosting those cells’ natural ability to clean up those clogs might hold the key to better treatment for such conditions.
That’s the key finding of new research from a University of Michigan Medical School physician scientist and his colleagues in California and the United Kingdom. They reported their latest findings this week in the journal Nature Chemical Biology.
Though the team showed the effect worked in animals and human neurons from stem cells, not patients, their discoveries point the way to find new medicines that boost the protein-clearing cleanup process.
The work also shows how an innovative microscope technique can help researchers see what’s going on inside brain cells, as they labor to clear out the protein buildup.
The researchers focused on a crucial cell-cleaning process called autophagy – a hot topic in basic medical research these days, as scientists discover its important role in many conditions. In autophagy, cells bundle unwanted materials up, break them down and push the waste products out.
In the newly published research, the team showed how the self-cleaning capacity of some brain cells gets overwhelmed if the cells make too much of an abnormal protein called TDP43. They found that cells vary greatly in how quickly their autophagy capacity gets swamped.
In brain cells that were made from stem cells derived from ALS patients, treatment with two drugs that stimulate autophagy led to longer cell survival (middle two lines).
But they also showed how three drugs that boost autophagy – speeding up the clean-out process – could keep the brain cells alive longer.
Longer-living, TDP43-clearing brain cells are theoretically what people with Lou Gehrig’s disease (amyotrophic lateral sclerosis or ALS) and certain forms of dementia (called frontotemporal) need. But only further research will show for sure.
Sami Barmada, M.D., Ph.D., the U-M neurologist and scientist who is first author of the new study, says the new findings are encouraging – and so is the success of a microscope technique used in the research. His new lab, in the U-M Department of Neurology, is continuing to refine ways to view the inner workings of nerve cells.
“Using this new visualization technique, we could truly see how the protein was being cleared, and therefore which compounds could enhance the pace of clearance and shorten the half-life of TDP43 inside cells,” he says. “This allowed us to see that increased autophagy was directly related to improved cell survival.”
Barmada worked on the team at the Gladstone Institutes and the University of California San Francisco headed by Steven Finkbeiner, M.D., Ph.D., that published the new findings. The team used stem cells derived from the cells of people who have ALS to grow neurons and astrocytes – the two types of brain cell most crucial to normal brain function.
Because he both sees patients in clinic and studies neurological disease in the laboratory, Barmada brings a special perspective to the research.
At U-M, he specializes in treating patients who have neurological diseases that affect both thinking and muscle control. About a third of ALS patients develop signs of frontotemporal dementia, also called FTD – and about 10 percent of people with FTD also have a motor neuron disease that affects their brain’s ability to control muscle movement.
One of the drugs tested in the study, an antipsychotic drug developed in the 1960s to treat people with schizophrenia, had actually shown some anti-dementia promise in human ALS patients, but comes with many side effects. Barmada notes that Finkbeiner’s team at the Gladstone Institute is already working to identify other compounds that could produce the effect with fewer side effects.
Interestingly, small studies have suggested that people with schizophrenia who take antipsychotic drugs are much less likely to develop ALS.
Barmada’s work at U-M now focuses on the connection between brain cells’ ability to clear abnormal proteins. He also studies the cells’ regulation of RNA molecules created as part of expressing protein-encoding genes. Looking further upstream in the protein-producing process could yield further clues to why disease develops and what can be done about it, he says.
(Source: uofmhealth.org)
Findings point toward one of first therapies for Lou Gehrig’s disease
Researchers have determined that a copper compound known for decades may form the basis for a therapy for amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease.
In a new study just published in the Journal of Neuroscience, scientists from Australia, the United States (Oregon), and the United Kingdom showed in laboratory animal tests that oral intake of this compound significantly extended the lifespan and improved the locomotor function of transgenic mice that are genetically engineered to develop this debilitating and terminal disease.
In humans, no therapy for ALS has ever been discovered that could extend lifespan more than a few additional months. Researchers in the Linus Pauling Institute at Oregon State University say this approach has the potential to change that, and may have value against Parkinson’s disease as well.
“We believe that with further improvements, and following necessary human clinical trials for safety and efficacy, this could provide a valuable new therapy for ALS and perhaps Parkinson’s disease,” said Joseph Beckman, a distinguished professor of biochemistry and biophysics in the OSU College of Science.
“I’m very optimistic,” said Beckman, who received the 2012 Discovery Award from the OHSU Medical Research Foundation as the leading medical researcher in Oregon.
ALS was first identified as a progressive and fatal neurodegenerative disease in the late 1800s and gained international recognition in 1939 when it was diagnosed in American baseball legend Lou Gehrig. It’s known to be caused by motor neurons in the spinal cord deteriorating and dying, and has been traced to mutations in copper, zinc superoxide dismutase, or SOD1. Ordinarily, superoxide dismutase is an antioxidant whose proper function is essential to life.
When SOD1 is lacking its metal co-factors, it “unfolds” and becomes toxic, leading to the death of motor neurons. The metals copper and zinc are important in stabilizing this protein, and can help it remain folded more than 200 years.
“The damage from ALS is happening primarily in the spinal cord and that’s also one of the most difficult places in the body to absorb copper,” Beckman said. “Copper itself is necessary but can be toxic, so its levels are tightly controlled in the body. The therapy we’re working toward delivers copper selectively into the cells in the spinal cord that actually need it. Otherwise, the compound keeps copper inert.”
“This is a safe way to deliver a micronutrient like copper exactly where it is needed,” Beckman said.
By restoring a proper balance of copper into the brain and spinal cord, scientists believe they are stabilizing the superoxide dismutase in its mature form, while improving the function of mitochondria. This has already extended the lifespan of affected mice by 26 percent, and with continued research the scientists hope to achieve even more extension.
The compound that does this is called copper (ATSM), has been studied for use in some cancer treatments, and is relatively inexpensive to produce.
“In this case, the result was just the opposite of what one might have expected,” said Blaine Roberts, lead author on the study and a research fellow at the University of Melbourne, who received his doctorate at OSU working with Beckman.
“The treatment increased the amount of mutant SOD, and by accepted dogma this means the animals should get worse,” he said. “But in this case, they got a lot better. This is because we’re making a targeted delivery of copper just to the cells that need it.
“This study opens up a previously neglected avenue for new disease therapies, for ALS and other neurodegenerative disease,” Roberts said.
(Source: oregonstate.edu)