Tag Archives: #ALS

Johns Hopkins Medicine Suggests Eliminating Nerve Cell Protein May Stop ALS, Dementia (Neuroscience)

Amyotrophic lateral sclerosis (ALS), commonly known as “Lou Gehrig’s disease,” is a devastating neurodegenerative illness that causes nerve cells in the brain and the spinal cord to atrophy (waste away), usually resulting in dementia. Ninety percent of ALS cases are sporadic, with no known genetic mutation responsible, while the remaining 10 percent are genetically passed from parent to child. Now, Johns Hopkins Medicine researchers have identified a defective cellular pathway that initiates nerve cell breakdown and may be tied to both forms of the disease. They also suggest that eliminating charge multivesicular body protein 7 (CHMP7), the wayward protein responsible for the broken pathway, might provide a future means of treating ALS and dementia.

Led by Jeffrey Rothstein M.D., Ph.D., director of the Pedersen Brain Science Institute and the Robert Packard Center for ALS Research, and professor of neurology and neuroscience at the Johns Hopkins University School of Medicine, and senior postdoctoral fellow Alyssa Coyne, Ph.D., the research team studied CHMP7 within an area of a nerve cell known as the nuclear pore. The nuclear pore — a large, highly organized complex of different proteins — serves as the gatekeeper for the nucleus, the cell’s control center, by governing the in-and-out movement of genetic material (RNA) and proteins. Previous studies by Rothstein’s team showed that when this process goes awry — which is said to be dysregulated — it can result in the development of either the familial or inherited forms of ALS and dementias.

However, it has remained unknown why this dysregulation occurs, how it starts the chain of events leading to ALS and if it occurs in the far more common sporadic forms of ALS and dementia.

The Johns Hopkins Medicine study, published July 28, 2021, in the journal Science Translational Medicine, evaluated why the nuclear pore starts to degrade in patients with ALS and dementia, and the role of CHMP7 in that destruction.

The researchers found that CHMP7 protein accumulates specifically within the nucleus of neurons, starting a cascade of events that leads to nuclear pore injury. This, in turn, causes dysregulation of essential proteins in the cell — including one called TAR DNA binding protein 43 (TDP-43), where the dysregulated form is seen in both sporadic and familial ALS — and ultimately, cell death.

“Think of it like an engine that’s starting to lose parts,” Rothstein says. “If CHMP7 is making the nuclear pore start to degrade, what would happen if we took that insult away?”

To find the answer, Rothstein and his colleagues eliminated the CHMP7 protein with antisense technology, a new and promising tool for controlling gene expression (production of a protein) in a cell. Using synthetic antisense oligonucleotides (fragments of genetic material), the researchers targeted the CHMP7 gene at the level of messenger RNA — which codes for CHMP7 protein to be made — rather than changing the DNA — which provides the code. This inhibited the CHMP7 gene from producing its protein, and in turn, the researchers found it prevented nuclear pore degradation, subsequent cellular dysfunction and cell death. With the pore stable, they believe that the conditions potentially leading to ALS cannot be triggered.

“We’re essentially preventing the biological events that give birth to ALS,” Rothstein says.

He says the next steps in the research are to determine if this discovery can be applied to a potential ALS therapy in humans. The team also hopes to learn what causes CHMP7 to become dysregulated in patients with ALS.

Featured image: Johns Hopkins Medicine researchers have shown that blocking production of a protein, CHMP7, in nerve cell nuclei enables other proteins (Nuc50 and Pom121) to keep nuclear pores (passageways in and out of the nucleus) functional and prevent nerve cell death — and perhaps prevent amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Graphic shows that as CHMP7 decreases, the levels of Nup50 and Pom121 increase (more green color indicates more protein). Credit: Robert Packard Center for ALS Research, Johns Hopkins Medicine

Reference: Alyssa Coyne et al., “Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS”, Science Translational Medicine  28 Jul 2021: Vol. 13, Issue 604, eabe1923 DOI: https://doi.org/10.1126/scitranslmed.abe1923

Provided by Johns Hopkins University School of Medicine

Researchers Identify A Cellular Defect Common to Familial and Sporadic Forms of ALS (Neuroscience)

NIH-funded study may point to possible therapeutic target for the disease.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal degenerative disease affecting the nerve cells in the brain and spinal cord responsible for controlling voluntary muscle movement. “Sporadic” or non-inherited ALS, accounts for roughly 90% percent of cases, and 10% of cases are due to known genetic mutations.  By studying lab-grown neurons derived from skin or blood cells from 10 normal controls, eight with an ALS causing mutation, and 17 with non-inherited ALS, researchers have found a possible starting point for the dysfunction that causes the disease. The study, which was published in Science Translational Medicine was funded in part by the National Institute for Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.

Using a library of ALS patient-derived cells, the research team led by Jeffrey Rothstein, M.D., Ph.D., at Johns Hopkins University School of Medicine, Baltimore, developed induced pluripotent stem cell (iPSC)-derived neurons from the patients’ cultured cells to discover a common defect regardless of whether the cell came from persons with inherited or non-inherited ALS. They report that in ALS nerve cells, there is an accumulation of a protein called CHMP7 in the nucleus of cultured nerve cells as well as in ALS samples from the brain region that controls movement. Treatments that decrease the amount of CHMP7 in the cultured cells prevented a series of abnormalities that are characteristic of ALS.

“There is considerable interest in identifying new therapeutic targets for ALS, particularly for the sporadic form of the disorder,” said Amelie Gubitz, Ph.D., program director, NINDS. “Gene-targeting strategies like the one shown here now allow us to move from biological discovery straight to therapy development.”

This study builds on an earlier paper by the Rothstein lab that looked at the most common genetic cause of ALS, a mutation in the C9orf72 gene (also referred to as the “C9 mutation”). There, they showed that the C9 mutation produced defects in a structure called the nuclear pore that is responsible for moving proteins and other molecules in and out of the nucleus of cells. Specifically, they found that certain proteins were absent from the pore, causing a domino-like effect in which the entire pore breaks apart.

“We knew from our previous work that the C9 mutation was producing defects in the nuclear pore, but we didn’t know why,” said Dr. Rothstein. “Here, we set out to answer the question of what was happening upstream of the pore defects by studying neurons derived from the cells of patients with ALS.”

Specifically, the researchers looked at nerve cells grown from induced pluripotent stem cells (iPSCs), which are a type of stem cell that can be created from samples of a person’s skin or blood. These cells behave very much like other stem cells in that they can be turned into many different cell types in a lab setting, including nerve cells. By working with Answer ALS, a national ALS biological data and iPSC effort run by Rothstein, the researchers were able to access iPSCs derived from both familial and sporadic ALS patients.

“One of the great advantages of iPSCs is that you can look at different times very much in the same way as you would study animal models at different ages,” said Dr. Rothstein. “We knew the time point where the nuclear pores began to degrade, and we were able to study neurons at earlier times to see what the cause could be.”

What they found was that the accumulation of CHMP7 within the nucleus occurred at least one week prior to the development of nuclear pore abnormalities. Normally, CHMP7 is quickly removed once it enters the nucleus, but in both C9 and sporadic ALS iPSC-derived neurons, the accumulation persisted. If an antisense oligonucleotide drug, which stops cells from manufacturing specific proteins, was used to decrease the amount of CHMP7 within the ALS neurons, the pore never degraded. Finally, if a mutated form of CHMP7 that cannot be removed from the nucleus was added to healthy neurons, the pore degraded much like what was seen in ALS neurons, suggesting that the presence of CHMP7 within the nuclei of neurons could be a lynchpin event in the development of the disease.

One abnormality common to all forms of ALS is the mislocalization of another protein, TDP-43. Normally found in the nucleus, TDP-43 leaks out into the surrounding cytoplasm in ALS where it clumps together into aggregates, leading to loss of function changes in various types of RNA, which are critical for the translation of certain genes into proteins. Eventually this is also seen in iPSC-derived neurons from both C9 and sporadic ALS patients. Following treatment with the antisense oligonucleotides for CHMP7, the TDP-43 mislocalization was no longer seen and the RNA defects were all corrected.

“These findings together allow us to put these abnormalities in sequence, where CHMP7 accumulation in the nucleus leads to nuclear pore injury, followed by TDP-43 mislocalization, and ultimately cell death,” said Dr. Rothstein. “This is not just limited to the C9 mutation; it is a fundamental pathway in sporadic ALS as well that can be treated with antisense oligonucleotides for CHMP7.”

Dr. Rothstein’s lab is currently investigating whether the antisense oligonucleotide drug could be developed into a treatment for both C9 and sporadic ALS patients. They are also continuing to study the initial accumulation of CHMP7 to determine what causes the mislocalization in the nucleus.

This study was supported by grants from the NIH (NS099114, NS091046, NS094239, NS122236), the U.S. Department of Defense, The Robert Packard Center for ALS Research Answer ALS Program, ALS Association, Muscular Dystrophy Association, Virginia Gentleman Foundation, F Prime, the Chan Zuckerberg Initiative, and an ALSA Milton Safenowitz Postdoctoral Fellowship.

Featured image: When CHMP7 accumulates in the nucleus, certain proteins become missing from nuclear pores (outlined in white). This causes the pores to break apart, leading to downstream effects that may cause ALS.Rothstein Lab

Reference: Coyne A.N. et al. Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Science Translational Medicine. July 28, 2021. DOI: 10.1126/scitranslmed.abe1923

Provided by NIH

Discovery of the Role of a Key Gene in the Development of ALS (Neuroscience)

Loss of function of the C9orf72 gene may affect communication between neurons and muscles

Amyotrophic lateral sclerosis, or ALS, attacks nerve cells known as motor neurons in the brain and spinal cord, gradually leading to paralysis. The loss of function of an important gene, C9orf72, may affect communication between motor neurons and muscles in people with this disease. These findings were revealed by the team of Dr Kessen Patten of the Institut national de la recherche scientifique (INRS) in the prestigious journal Communications Biology.

A mutation in the C9orf72 gene is the primary genetic cause of ALS. The mutation in C9orf72 consists of an expansion of a sequence of six DNA bases (GGGGCC) that is very unusual, going from a few copies (less than 20 in a healthy person) to more than 1000 copies. The mutation, in part resulting in a loss of function, may be responsible for 40% to 50% of hereditary cases of ALS, and 5% to 10% of cases without family history.

Dr Patten’s team investigated this gene’s loss of function in genetically modified zebrafish models. In their work, led by PhD student Zoé Butti, the group noted symptoms similar to ALS, namely motor disorders, muscle atrophy, loss of motor neurons, and mortality of individuals.

Synaptic transmission

The study showed the effect of the loss of function induced by the mutation of the C9orf72 gene on communication between motor neurons and muscles. “This synaptic dysfunction is observed in all people with the disease and occurs before the death of motor neurons,” noted the researcher and holder of the Anna Sforza Djoukhadjian Research Chair.

The research group also revealed the gene’s role on the protein TDP-43 (transactive response DNA binding protein 43) which plays an important role in ALS. The C9orf72 gene may affect the protein TDP-43’s location within the cell. “In approximately 97% of ALS patients, the TDP-43 protein is depleted from the nucleus and forms aggregates in the cytoplasm rather than being in the nucleus, as is the case in healthy people. We want to investigate this relationship between the two proteins further,” explained Professor Patten.

Now that the team has developed a model, it will be able to test therapeutic molecules. The aim is to find a drug to restore the synaptic connection between neurons and muscles. It may also lead to a therapeutic target to rectify the abnormality of the TDP-43 protein.

About the study

The article “Reduced C9orf72 function leads to defective synaptic vesicle release and neuromuscular dysfunction in zebrafish” by Zoé Butti, Yingzhou Edward Pan and Shunmoogum A. Patten, with the help of collaborator Dr Jean Giacomotto from the Queensland Brain Institute, was published in the journal Communications Biology. The study received financial support from the ALS Society of Canada, the Brain Canada Foundation, the Anna Sforza Djoukhadjian Research Chair fund, the Natural Sciences and Engineering Council of Canada, the Canada Foundation for Innovation, and the Canadian Institutes of Health Research.

Featured image: INRS Professor Kessen Patten, specialist in amyotrophic lateral sclerosis (ALS) and holder of the Anna Sforza Djoukhadjian Research Chair. © Christian Fleury

Provided by INRS

Brain-Computer Interface Turns Mental Handwriting Into Text (Neuroscience)

Study in a Sentence: Using an implanted sensor to record the brain signals associated with handwriting, scientists have developed a brain-computer interface (BCI) designed to restore the ability to communicate in real-time in people with spinal cord injuries and neurological disorders such as amyotrophic lateral sclerosis (ALS).

Healthy for Humans: Locked-in syndrome, commonly caused by a spinal cord injury, stroke, or last-stage ALS, is the paralysis of voluntary muscles, which impairs or prevents communication. By implanting two small sensors on a patient’s brain, researchers were able to decipher the brain activity associated with trying to write letters by hand. A machine-learning algorithm was used to identify letters as the patient attempted to write them, then the system displayed the text on a screen. 

Redefining Research: Other BCIs for restoring communication exist; however, they have shown to be imprecise and have several limitations. In this study, the participant was able to think about motions involved in writing letters and words by hand, which was found to be faster, more accurate, and easier to use than previous BCIs. Researchers hope this technology may one day help restore the ability to communicate in patients with locked-in syndrome.

Featured image credit: Getty images


Willett FR, Avansino DT, Hochberg LR. et al. High-performance brain-to-text communication via handwriting. Nature. 2021;593:249–254. https://doi.org/10.1038/s41586-021-03506-2

Provided by PCRM

A Distinctive Inflammatory Signature Found in a Genetic Form of ALS (Medicine)

Researchers find an increase in inflammatory molecules in serum and cerebrospinal fluid of C90RF72 patients, informing future anti-inflammatory therapies

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disease that strikes nearly 5,000 people in the U.S. every year. About 10% of ALS cases are inherited or familial, often caused by an error in the C9orf72 gene. Compared to sporadic or non-familial ALS, C90rf72 patients are considered to have a more aggressive disease course. Evidence points to the immune system in disease progression in C90rf72 patients, but we know little of what players are involved. New research from the Jefferson Weinberg ALS Center identified an increased inflammatory signal in C90rf72 patients compared to other ALS patients, pointing to immune characteristics that distinguish this subgroup of ALS patients and informing potential anti-inflammatory therapies. The study was published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration on April 30th, 2021.

In comprehensive analyses, the researchers collected cerebrospinal fluid (CSF), via a small puncture in the spine, as well as serum from 15 C9orf72 patients, 9 sporadic ALS patients and 14 control patients, and conducted a test to measure the levels of around 40 different immune molecules and chemicals. They found an increase in pro-inflammatory molecules in the serum and CSF of both sporadic and C9orf72 ALS patients compared to controls, but the increase was more pronounced in C9orf72 patients.

These findings point to important distinguishing characteristics of this subgroup of ALS patients, which could be detectable in a peripheral test of serum. Serum tests would be less invasive than testing CSF. The results also indicate that any future strategies for developing anti-inflammatory treatments would benefit from distinguishing the C9orf72 subtype from other types of ALS. The researchers are looking to build a bank of patient samples to continue studying key differences between patient subtypes.

“This is a step in better characterizing this sub-population of ALS patients,” says senior author Hristelina Ilieva, MD, PhD, assistant professor and medical director of the Weinberg ALS Center, “and an impetus to continue the search for biomarkers for this disease.”

The work was funded by an American Brain Foundation award. The authors report no conflict of interest.

Article Reference: Gabriel Pinilla, Anupama Kumar, Mary Kay Floaters, Carlos A Pardo, Jeffrey Rothstein, Hristelina Ilieva, “Increased synthesis of pro-inflammatory cytokines in C9ORF72 patients”, DOI: 10.1080/21678421.2021.1912100, Amyotroph Lateral Scler Frontotemporal Degener, 2021

Provided by Thomas Jefferson University

ALS Development Could Be Triggered by Loss Of Specific Network Connections in the Spinal Cord (Neuroscience)

The network connection between nerve cells in the spinal cord seems to play a critical role in the development of the severe disease ALS, a new study from the University of Copenhagen suggests. The study, which is based on a mouse model, may change the way we think about the disease, says researchers.

ALS is a very severe neurodegenerative disease in which nerve cells in the spinal cord controlling muscles and movement slowly die. There is no effective treatment and the average life expectancy after being diagnosed with ALS is usually short. Because of this, new knowledge about the disease is urgently needed.

Now, researchers from the University of Copenhagen have gained new insights about ALS, by investigating the early development of the disease in a mouse model.

“We have found that networks of nerve cells in the spinal cord called inhibitory interneurons lose connection to motor neurons, the nerve cells that directly control muscle contraction. We do not yet know if these changes cause the disease. But the loss of the inhibitory signal could explain why the motor neurons end up dying in ALS”, says first and co-corresponding author to the new study Ilary Allodi, Assistant Professor at the Department of Neuroscience.

A lot of ALS research have focused on the motor neurons themselves, but the research group at the University of Copenhagen had a different approach.

“It is only natural that motor neurons have received major attention. They control our muscles, which is the challenge for ALS patients. Here, we wanted to investigate the circuit of interneurons in the spinal cord because they determine the activity of motor neurons. Since we found that there is a loss of connections between inhibitory interneurons and motor neurons that happens before the motor neuron death, we think that this loss could be a possible explanation for why the motor neurons ends up dying in ALS patients”, says Ole Kiehn, senior, co-corresponding author and Professor at the Department of Neuroscience.

Fast-twitch first

In ALS patients, the degeneration typically starts with what is called the fast-twitch motor neurons and then goes on to other motor neurons. This means that certain muscles and bodily functions are affected before others. Normally, patients lose coordination and speed in movement before more basic functions such as breathing. This is mirrored in the new findings, according to the researchers.

“In our mouse model, we show that the loss of connection happens to fast motor neurons first and then slow motor neurons later on involve a particular type of inhibitory neurons, the so called V1 interneurons”, says Roser Montañana-Rosell, who is PhD student and shared first author on the study.

“The V1 interneuron connectivity loss is paralleled by the development of a specific locomotor deficit in the pre-symptomatic phase with lower speed and changes in limb coordination in the ALS mice that is dependent on V1 interneuron connections to motor neuron”, says Ole Kiehn. 

Expanding the window of opportunity

The researchers underline that the mechanisms should be investigated in human patients as well. However, they do not have any reason to believe that the same or similar biological mechanisms are not at play in humans.

Given the new understanding of the disease, Ilary Allodi hopes further research into the signaling process could reveal how to repair the nerve cell connection loss in ALS.

 “We definitely hope that our findings can contribute with a new way of thinking about ALS development. With a distinct focus on interneurons, we might be able, in future experiments, to increase the signaling processes from the interneurons to the motor neurons and prevent or delay the motor neuron degeneration from an early stage,” ends Ilary Allodi.

Read the entire study in Nature Communications: “Locomotor deficits in a mouse model of ALS are paralleled by loss of V1-interneuron connections onto fast motor neurons”

Featured image: The spinal cord of a mouse with ALS. The green cells are the inhibitory interneurons (Photo: Ilary Allodi)

Provided by University of Copenhagen

Scientists Discover A New Genetic Form of ALS in Children (Medicine)

NIH- and USU- led study links ALS to a fat manufacturing gene and maps out a genetic therapy

In a study of 11 medical-mystery patients, an international team of researchers led by scientists at the National Institutes of Health and the Uniformed Services University (USU) discovered a new and unique form of amyotrophic lateral sclerosis (ALS). Unlike most cases of ALS, the disease began attacking these patients during childhood, worsened more slowly than usual, and was linked to a gene, called SPTLC1, that is part of the body’s fat production system. Preliminary results suggested that genetically silencing SPTLC1 activity would be an effective strategy for combating this type of ALS.

“ALS is a paralyzing and often fatal disease that usually affects middle-aged people. We found that a genetic form of the disease can also threaten children. Our results show for the first time that ALS can be caused by changes in  the way the body metabolizes lipids,” said Carsten Bönnemann, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study published in Nature Medicine. “We hope these results will help doctors recognize this new form of ALS and lead to the development of treatments that will improve the lives of these children and young adults. We also hope that our results may provide new clues to understanding and treating other forms of the disease.”

Dr. Bönnemann leads a team of researchers that uses advanced genetic techniques to solve some of the most mysterious childhood neurological disorders around the world. In this study, the team discovered that 11 of these cases had ALS that was linked to variations in the DNA sequence of SPLTC1, a gene responsible for manufacturing a diverse class of fats called sphingolipids.

In addition, the team worked with scientists in labs led by Teresa M. Dunn, Ph.D., professor and chair at USU, and Thorsten Hornemann, Ph.D., at the University of Zurich in Switzerland. Together they not only found clues as to how variations in the SPLTC1 gene lead to ALS but also developed a strategy for counteracting these problems.

The study began with Claudia Digregorio, a young woman from the Apulia region of Italy. Her case had been so vexing that Pope Francis imparted an in-person blessing on her at the Vatican before she left for the United States to be examined by Dr. Bönnemann’s team at the NIH’s Clinical Center.

Like many of the other patients, Claudia needed a wheelchair to move around and a surgically implanted tracheostomy tube to help with breathing. Neurological examinations by the team revealed that she and the others had many of the hallmarks of ALS, including severely weakened or paralyzed muscles. In addition, some patients’ muscles showed signs of atrophy when examined under a microscope or with non-invasive scanners.

Nevertheless, this form of ALS appeared to be different. Most patients are diagnosed with ALS around 50 to 60 years of age. The disease then worsens so rapidly that patients typically die within three to five years of diagnosis. In contrast, initial symptoms, like toe walking and spasticity, appeared in these patients around four years of age. Moreover, by the end of the study, the patients had lived anywhere from five to 20 years longer.

“These young patients had many of the upper and lower motor neuron problems that are indicative of ALS,” said Payam Mohassel, M.D., an NIH clinical research fellow and the lead author of the study. “What made these cases unique was the early age of onset and the slower progression of symptoms. This made us wonder what was underlying this distinct form of ALS.”

The first clues came from analyzing the DNA of the patients. The researchers used next-generation genetic tools to read the patients’ exomes, the sequences of DNA that hold the instructions for making proteins. They found that the patients had conspicuous changes in the same narrow portion of the SPLTC1 gene. Four of the patients inherited these changes from a parent. Meanwhile, the other six cases appeared to be the result of what scientist call “de novo” mutations in the gene. These types of mutations can spontaneously occur as cells rapidly multiply before or shortly after conception.

Mutations in SPLTC1 are also known to cause a different neurological disorder called hereditary sensory and autonomic neuropathy type 1 (HSAN1). The SPLTC1 protein is a subunit of an enzyme, called SPT, which catalyzes the first of several reactions needed to make sphingolipids. HSAN1 mutations cause the enzyme to produce atypical and harmful versions of sphingolipids.

At first, the team thought the ALS-causing mutations they discovered may produce similar problems. However, blood tests from the patients showed no signs of the harmful sphingolipids.

“At that point, we felt like we had hit a roadblock. We could not fully understand how the mutations seen in the ALS patients did not show the abnormalities expected from what was known about SPTLC1 mutations,” said Dr. Bönnemann. “Fortunately, Dr. Dunn’s team had some ideas.”

For decades Dr. Dunn’s team had studied the role of sphingolipids in health and disease. With the help of the Dunn team, the researchers reexamined blood samples from the ALS patients and discovered that the levels of typical sphingolipids were abnormally high. This suggested that the ALS mutations enhanced SPT activity.

Similar results were seen when the researchers programmed neurons grown in petri dishes to carry the ALS-causing mutations in SPLTC1. The mutant carrying neurons produced higher levels of typical sphingolipids than control cells. This difference was enhanced when the neurons were fed the amino acid serine, a key ingredient in the SPT reaction.

Previous studies have suggested that serine supplementation may be an effective treatment for HSAN1. Based on their results, the authors of this study recommended avoiding serine supplementation when treating the ALS patients.

Next, Dr. Dunn’s team performed a series of experiments which showed that the ALS-causing mutations prevent another protein called ORMDL from inhibiting SPT activity.

“Our results suggest that these ALS patients are essentially living without a brake on SPT activity. SPT is controlled by a feedback loop. When sphingolipid levels are high then ORMDL proteins bind to and slow down SPT. The mutations these patients carry essentially short circuit this feedback loop,” said Dr. Dunn. “We thought that restoring this brake may be a good strategy for treating this type of ALS.”

To test this idea, the Bönnemann team created small interfering strands of RNA designed to turn off the mutant SPLTC1 genes found in the patients. Experiments on the patients’ skin cells showed that these RNA strands both reduced the levels of SPLTC1 gene activity and restored sphingosine levels to normal.

“These preliminary results suggest that we may be able to use a precision gene silencing strategy to treat patients with this type of ALS. In addition, we are also exploring other ways to step on the brake that slows SPT activity,” said Dr. Bonnemann. “Our ultimate goal is to translate these ideas into effective treatments for our patients who currently have no therapeutic options.”


Mohassel, P. et al., Childhood Amyotrophic Lateral Sclerosis Caused by Excess Sphingolipid Synthesis. Nature Medicine, May 31, 2021 DOI: 10.1038/s41591-021-01346-1

This study was supported by the NIH Intramural Research Program at the NINDSNIH grants (NS10762, NS072446); the U.S. Department of Defense’s Congressionally Directed Medical Research Programs (W81XWH-20-1-0219); the Swiss National Foundation (31003A_179371); the Deater foundation, Inc. The views expressed here do not represent those of the Department of Defense.

Featured image: NIH researchers discovered a new form of ALS that begins in childhood. The study linked the disease to a gene called SPLTC1. As part of the study, NIH senior scientist Carsten Bonnemann, M.D., (right) examined Claudia Digregorio (left), a patient from the Apulia region of Italy. © Courtesy of the NIH/NINDS.

Provided by NINDS

Protein Linked To ALS/Ataxia Could Play Key Role In Other Neurodegenerative Disorders (Neuroscience)

Neurological disorders are the number one cause of disability in the world, leading to seven million deaths each year. Yet few treatments exist for these diseases, which progressively diminish a person’s ability to move and think. 

Now, a new study suggests that some of these neurological disorders share a common underlying thread. Staufen1, a protein that accumulates in the brains of patients with certain neurological conditions, is linked to amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, along with other neurological disorders, including Alzheimer’s, Parkinson’s, and Huntington’s disease, according to University of Utah Health scientists.

The findings connect Staufen1 to the emerging concept that neurodegenerative diseases are linked to malfunctions in the way cells cope with cellular stress. These results, based on laboratory studies of human tissue and mouse models, suggest that targeting Staufen1 could eventually lead to therapeutic interventions for a number of these disorders.

The study appears in Annals of Neurology.

“Neurodegenerative diseases are a major cause of morbidity and mortality,” says Stefan Pulst, M.D., Dr. Med, chair of the Department of Neurology at the University of Utah School of Medicine and senior researcher on the study. “Unfortunately, at this time, we have few, if any, disease-modifying therapies. This finding provides new insight into the pathogenesis of these disorders and potentially provides us with a new target for treatment.”

In previous research, the scientists found that Staufen1 accumulates in cells of patients with ALS and cerebellar ataxia, a rare condition that causes patients to lose control of movement. They found that Staufen1 binds to a protein that is both a risk factor for ataxia and a risk factor for ALS. Together, along with other proteins, they form dense disease-related clusters called stress granules that can disrupt normal cellular function. However, when Staufen1 was lowered in the brains of mice, it not only improved the pathology of disease but also rid cells of stress granules.

Stefan Pulst, M.D., Dr. Med, (left) chair of the Department of Neurology at the University of Utah School of Medicine, and Daniel Scoles, Ph.D., associate professor of neurology at U of U Health.Photo credit: Charile Ehlert

In their new study, Pulst and colleagues sought to determine if Staufen1 overabundance was a factor in the development of other neurological disorders. To do it, they conducted laboratory experiments on skin cells and spinal cord tissues collected from 12 patients with several different neurodegenerative diseases. They also examined the effects of Staufen1 on neurodegeneration in two animal models.

“We found that Staufen1 protein levels were vastly increased in all of the disease models we examined,” Pulst says. “In our laboratory animals, levels of this protein were three- to five-fold higher than in control animals. That’s not subtle. If a protein is changed that much, it probably isn’t good for any cell, particularly a neuron.”

Digging deeper, the researchers found that Staufen1 has an important interaction with another protein called mTOR, a master regulator of many functions in the body that plays a key role in a process called autophagy. Autophagy, or “self-digestion,” is a self-preservation mechanism that the body uses to remove dysfunctional cells.  

The new study suggests that the complex relationship between Staufen1, mTOR, and autophagy could be a driving factor in the onset of several neurogenerative diseases, according to Daniel Scoles, Ph.D., study co-author and associate professor of neurology at U of U Health.

“When Staufen1 is increased, it actually impairs autophagy,” Scoles says. “But we also know that autophagy can degrade Staufen1. It’s a vicious cycle that can have a bad outcome for patients.”

Based on these findings, Pulst and Scoles are hopeful that they can develop a medication to reduce Staufen1 levels in people at risk for sporadic ALS, the most common form of ALS, in which the causes of the disease are unknown.   

If lowering Staufen1 is effective for ALS, it could eventually lead to new therapeutic approaches for the treatment of Alzheimer’s disease and other Staufen1-related disorders, the researchers say.

 In addition to Drs. Pulst and Scoles, U of U Health scientists Sharan Paul, Warunee Dansithong, Karla P. Figueroa, and Mandi Gandelman contributed to this research. The study, “Staufen1 in Human Neurodegeneration appears in the Annals of Neurology. The National Institute of Neurological and Stroke, Target ALS Foundation and Harrington Discovery Institute supported this research.

Featured image: A new University of Utah Health study suggests that Staufen1, a protein that accumulates in the brains of.certain patients, is linked to several neurodegenerative disorders. Photo credit: Getty Images

Reference: Paul, S., Dansithong, W., Figueroa, K.P., Gandelman, M., Scoles, D.R. and Pulst, S.M. (2021), Staufen1 in Human Neurodegeneration. Ann Neurol. https://doi.org/10.1002/ana.26069

Provided by Health University of Utah

New Type of Cell Contributes To Increased Understanding of ALS (Medicine)

The causes of the serious muscle disease ALS still remain unknown. Now, researchers at Karolinska Institutet and KTH Royal Institute of Technology, among others, have examined a type of cell in the brain blood vessels that could explain the unpredictable disease origins and dynamics. The results indicate a hitherto unknown connection between the nervous and vascular systems. The study, which is published in Nature Medicine, has potential implications for earlier diagnoses and future treatments.

ALS (amyotrophic lateral sclerosis) is a neurodegenerative disease of the motor neurons that eventually causes muscular atrophy, paralysis and death. There is currently no cure.

The cause of ALS is only understood in the 5 to 10 per cent of patients who have an inherited form of the disease. To help in its early detection and to develop efficacious therapies, researchers are avidly seeking a clearer picture of the disease’s pathogenesis.

ALS patients demonstrate high variability of age at onset, non-motor symptoms and survival. In recent years, research has shifted focus from neurological explanations to these differences, and has taken an interest, for example, in the cerebral vascular system, which delivers oxygen and nutrients to brain tissue.

Anna Månberg, researcher at the Department of Protein Science, at KTH Royal Institute of Technology and SciLifeLab. © KTH Royal Institute of Technology

Researchers at Karolinska Institutet, KTH Royal Institute of Technology, SciLifeLab, London’s Imperial College and Umeå University have now studied whether a possible connection exists between perivascular fibroblast cells and the time of disease onset and survival.

Studies on mice with ALS showed that genes for perivascular fibroblasts were active already in an early asymptomatic stage of the disease and months before neuronal damage began to appear.

The researchers then examined the levels of a large number of potential marker proteins in the plasma of 574 patients with a recent ALS diagnosis and 504 healthy controls from four countries.

Their results suggest a correlation between elevated levels of the protein marker SPP1 for perivascular fibroblasts and an aggressive disease process and shorter survival. This is the first time a connection between the vascular and nervous systems in sporadic ALS has been observed.

“It is exciting to see how the results from our protein profiling could be connected to the long range of cellular and molecular analysis that we have done and reveal the identified association to disease progression,” says the first author Anna Månberg, researcher at the Department of Protein Science, at KTH and SciLifeLab.

“Our results indicate that vascular events are a factor in the disease’s heterogeneity and can improve our knowledge of early stage ALS,” says the study’s last and senior author Sebastian Lewandowski, researcher at the Department of Clinical Neuroscience and the Centre for Molecular Medicine at Karolinska Institutet. “More studies are now needed on vascular disease mechanisms for better prognostic tools and future treatments.”

The research was financed by the Olle Engkvist Foundation, the Ulla-Carin Lindquist Foundation for ALS Research, the Swedish FTD Initiative and others, and received strategic support from the Knut and Alice Wallenberg Foundation and the Erling-Persson Family Foundation for the KTH Center for Applied Precision Medicine (KCAP). See the paper for further details of the researchers’ other work.

Featured image: Sebastian Lewandowski, researcher at the Department of Clinical Neuroscience, Karolinska Institutet. © Ulf Sirborn

Publication: “Altered perivascular fibroblast activity precedes ALS disease onset”, Anna Månberg, Nathan Skene, Folkert Sanders, Marta Trusohamn, Julia Remnestål, Anna Szczepi?ska, Inci Sevval Aksoylu, Peter Lönnerberg, Lwaki Ebarasi, Stefan Wouters, Manuela Lehmann, Jennie Olofsson, Inti Von Gohren Antequera, Aylin Domaniku, Maxim De Schaepdryver, Joke De Vocht, Koen Poesen, Mathias Uhlén, Jasper Anink, Caroline Mijnsbergen, Hermieneke Vergunst-Bosch, Annemarie Hübers, Ulf Kläppe, Elena Rodriguez-Vieitez, Jonathan D. Gilthorpe, Eva Hedlund, Robert A. Harris, Eleonora Aronica, Philip Van Damme, Albert Ludolph, Jan Veldink, Caroline Ingre, Peter Nilsson, Sebastian A. Lewandowski. Nature Medicine, online 15 April 2021, doi: 10.1038/s41591-021-01295-9.

Provided by Karolinska Institute