nerve cells

Stanford scientists link problems in nerve cells to schizophrenia

/ Yimy Villa / Leave a comment
A spherical cluster of hundreds of thousands of brain cells cultured in a lab dish. A team of researchers studied such neuronal clusters to better understand schizophrenia.
Image Credit: Pasca lab

The neurological origins of mental illness continue to remain a mystery and along with it any potential treatments for these conditions. However, Dr. Sergiu Pasca and his team at Stanford University have come one step closer to unlocking these mysteries for schizophrenia, a mental disorder characterized by disruptions in thought processes, perceptions, emotional responsiveness, and social interactions. 

A common genetic defect called 22q11.2 deletion syndrome, or 22q11DS for short, has been linked to an astonishing 30-fold increased risk for developing schizophrenia. With help from CIRM funding, Dr. Pasca and his team have linked this genetic defect to an electrical defect in nerve cells.

To look at this more closely, the Stanford team generated tiny clusters of brain cells, called cortical spheroids which contain brain nerve cells, in a dish using skin cells from 22q11DS carriers and those from normal patients. The team then measured the resting membrane potential of these nerve cells, which is the voltage difference between the inner and outer part of the cell. This measurement is important because it keeps the nerve cells ready to fire while also preventing them from firing at random.

Dr. Pasca and his team found abnormal levels of resting membrane potential in nerve cells in the cortical spheroids made from 22q11DS carriers. They also found that the the 22q11DS-derived nerve cells spontaneously fired four times as frequently as nerve cells derived from normal patients. What’s even more promising is that the team found that treating the 22q11DS-derived nerve cells with any of three different antipsychotic drugs effectively reversed the defects in resting membrane potential and helped in prevent spontaneous firing.

Dr. Sergiu Pasca

In a press release, Dr. Pasca elaborated more on the team’s findings.

“We can’t test hallucinations in a dish. But the fact that the cellular malfunctions we identified in a dish were reversed by drugs that relieve symptoms in people with schizophrenia suggests that these cellular malfunctions could be related to the disorder’s behavioral manifestations.”

The full results of this study were published in Nature Medicine.

Stem cell model reveals deeper understanding into “ALS resilient” neurons

/ Yimy Villa / Leave a comment
A descriptive illustration of Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s Disease. Courtesy of ALS Foundation website.

Understanding the basic biology of how a cell functions can be crucial to being able to better understand a disease and unlock a potential approach for a treatment. Stem cells are unique in that they give scientists the opportunity to create a controlled environment of cells that might be otherwise difficult to study. Dr. Eva Hedlund and a team of researchers at the Karolinska Institute in Sweden utilize a stem cell model approach to uncover findings related to Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s Disease.

ALS is a progressive neurodegenerative disease that destroys motor neurons, a type of nerve cell, that are important for voluntary muscle movement. When motor neurons can no longer send signals to the muscles, the muscles begin to deteriorate, a process formally known as atrophy. The progressive atrophy leads to muscle paralysis, including those in the legs and feet, arms and hands, and those that control swallowing and breathing. It affects about 30,000 people in the United States alone, with 5,000 new cases diagnosed each year. There is currently no cure.

In a previous study, researchers at the Karolinska Institute were able to successfully create oculomotor neurons from embryonic stem cells. For reasons not yet fully understood, oculomotor neurons are “ALS resilient” and can survive all stages of the disease.

In the current study, published in Stem Cell Reports, Dr. Hedlund and her team found that the oculomotor neurons they generated appeared more resilient to ALS-like degeneration when compared to spinal cord motor neurons, something commonly observed in humans. Furthermore, they discovered that their “ALS resilient” neurons generated from stem cells activate a survival-enhancing signal known as Akt, which is common in oculomotor neurons in humans and could explain their resilience. These results could potentially aid in identifying genetic targets for treatments protecting sensitive neurons from the disease.

In a press release, Dr. Hedlund is quoted as saying,

“This cell culture system can help identify new genes contributing to the resilience in oculomotor neurons that could be used in gene therapy to strengthen sensitive motor neurons.”

CIRM is currently funding two clinical trials for ALS, one of which is being conducted by Cedars-Sinai Medical Center and the other by Brainstorm Cell Therapeutics. The latter of the trials is currently recruiting patients and information on how to enroll can be found here.

Salk Scientists Unlock New Secrets of Autism Using Human Stem Cells

/ Karen Ring / Leave a comment

Autism is a complex neurodevelopmental disorder whose mental, physical, social and emotional symptoms are highly variable from person to person. Because individuals exhibit different combinations and severities of symptoms, the concept of autism spectrum disorder (ASD) is now used to define the range of conditions.

There are many hypotheses for why autism occurs in humans (which some estimates suggest now affects around 3.5 million people in the US). Some of the disorders are thought to be at the cellular level, where nerve cells do not develop normally and organize properly in the brain, and some are thought to be at the molecular level where the building blocks in cells don’t function properly. Scientists have found these clues by using tools such as studying human genetics and animal models, imaging the brains of ASD patients, and looking at the pathology of ASD brains to see what has gone wrong to cause the disease.

Unfortunately, these tools alone are not sufficient to recreate all aspects of ASD. This is where cellular models have stepped in to help. Scientists are now developing human stem cell derived models of ASD to create “autism in a dish” and are finding that the nerve cells in these models show characteristics of these disorders.

Stem cell models of autism and ASD

We’ve reported on some of these studies in previous blogs. A group from UCSD lead by CIRM grantee Alysson Muotri used induced pluripotent stem cells or iPS cells to model non-syndromic autism (where autism is the primary diagnosis). The work has been dubbed the “Tooth Fairy Project” – parents can send in their children’s recently lost baby teeth which contain cells that can be reprogrammed into iPS cells that can then be turned into brain cells that exhibit symptoms of autism. By studying iPS cells from individuals with non-syndromic autism, the team found a mutation in the TRPC6 gene that was linked to abnormal brain cell development and function and is also linked to Rett syndrome – a rare form of autism predominantly seen in females.

Another group from Yale generated “mini-brains” or organoids derived from the iPS cells of ASD patients. They specifically found that ASD mini-brains had an increased number of a type of nerve cell called inhibitory neurons and that blocking the production of a protein called FOXG1 returned these nerve cells back to their normal population count.

Last week, a group from the Salk Institute in collaboration with scientists at UC San Diego published findings about another stem cell model for ASD that offers new clues into the early neurodevelopmental defects seen in ASD patients.  This CIRM-funded study was led by senior author Rusty Gage and was published last week in the Nature journal Molecular Psychiatry.

Unlocking clues to autism using patient stem cells

Gage and his team were fascinated by the fact that as many as 30 percent of people with ASD experience excessive brain growth during early in development. The brains of these patients have more nerve cells than healthy individuals of the same age, and these extra nerve cells fail to organize properly and in some cases form too many nerve connections that impairs their overall function.

To understand what is going wrong in early stages of ASD, Gage generated iPS cells from ASD individuals who experienced abnormal brain growth at an early age (their brains had grown up to 23 percent faster when they were toddlers compared to normal toddlers). They closely studied how these ASD iPS cells developed into brain stem cells and then into nerve cells in a dish and compared their developmental progression to that of healthy iPS cells from normal individuals.

Neurons derived from people with ASD (bottom) form fewer inhibitory connections (red) compared to those derived from healthy individuals (top panel). (Salk Institute)

Neurons derived from people with ASD (bottom) form fewer inhibitory connections (red) compared to those derived from healthy individuals (top panel). (Salk Institute)

They quickly observed a problem with neurogenesis – a term used to describe how brain stem cells multiply and create new nerve cells in the brain. Brain stem cells derived from ASD iPS cells displayed more neurogenesis than normal brain stem cells, and thus were creating an excess amount of nerve cells. The scientists also found that the extra nerve cells failed to form as many synaptic connections with each other, an essential process that allows nerve cells to send signals and form a functional network of communication, and also behaved abnormally and overall had less activity compared to healthy neurons. Interestingly, they saw fewer inhibitory neuron connections in ASD neurons which is contrary to what the Yale study found.

The abnormal activity observed in ASD neurons was partially corrected when they treated the nerve cells with a drug called IGF-1, which is currently being tested in clinical trials as a possible treatment for autism. According to a Salk news release, “the group plans to use the patient cells to investigate the molecular mechanisms behind IGF-1’s effects, in particular probing for changes in gene expression with treatment.”

Will stem cells be the key to understanding autism?

It’s clear that human iPS cell models of ASD are valuable in helping tease apart some of the mechanisms behind this very complicated group of disorders. Gage’s opinion is that:

“This technology allows us to generate views of neuron development that have historically been intractable. We’re excited by the possibility of using stem cell methods to unravel the biology of autism and to possibly screen for new drug treatments for this debilitating disorder.”

However, to me it’s also clear that different autism stem cell models yield different results, but these differences are likely due to which populations the iPS cells are derived from. Creating more cell lines from different ASD subpopulations will surely answer more questions about the developmental differences and differences in brain function seen in adults.

Lastly, one of the co-authors on the study, Carolina Marchetto, made a great point in the Salk news release by acknowledging that their findings are based on studying cells in a dish, not actual patient’s brains. However, Marchetto believes that these cells are useful tools for studying autism:

“It never fails to amaze me when we can see similarities between the characteristics of the cells in the dish and the human disease.”

Rusty Gage and Carolina Marchetto. (Salk Institute)

Rusty Gage and Carolina Marchetto. (Salk Institute)

Related Links

Brain Stem Cells in a Dish to the Rescue

/ Karen Ring / Leave a comment

braindish

Image credit: CureCDKL5.org

The best way to impress your friends at the next party you attend might be to casually mention that scientists can grow miniature brain models in a dish using human stem cells. Sure, that might scare away some people, but when you explain how these tiny brain models can be used to study many different neurological diseases and could help identify new therapies to treat these diseases, your social status could sky rocket.

Recently, a group at UC San Diego used human stem cells to model a rare neurological disorder and identified a drug molecule that might be able to fix it. This work was funded in part by CIRM, and it was published today in the journal Molecular Psychiatry.

The disorder is called MECP2 duplication syndrome. It’s caused by a duplication of the MECP2 gene located in the X chromosome, and is genetically inherited as an X-linked disorder, meaning the disease is much more common in males. Having extra copies of this gene causes a number of unfortunate symptoms including reduced muscle tone (hypotonia), intellectual disabilities, impaired speech, seizures, and developmental delays, to name a few. So far, treatments for this disorder only help ease the symptoms and do not cure the disease.

The group from UCSD decided to model this disease using induced pluripotent stem cells (iPSCs) derived from patients with MECP2 duplication syndrome. iPSCs can form any cell type in the body, and the group used this to their advantage by coaxing the iPSCs into the specific type of nerve cell affected by the disorder. Their hard work was rewarded when they observed that the diseased nerve cells acted differently than normal nerve cells without the disease.

In fact, the diseased nerve cells generated more connections with other nearby nerve cells, and this altered their ability to talk to each other and perform their normal functions. The senior author Alysson Muotri described the difference as an “over-synchronization of the neuronal networks”, meaning that they were more active and tended to fire their signals in unison.

After establishing a relevant nerve cell model of MECP2 duplication disorder, the group tested out a library of drug molecules and identified a new drug candidate that was able to rescue the diseased nerve cells from their “over-synchronized” activity.

The senior author Alysson Muotri commented on the study in a press release:

Alysson Muotri (Photo by David Ahntholz)  

This work is encouraging for several reasons. First, this compound had never before been considered a therapeutic alternative for neurological disorders. Second, the speed in which we were able to do this. With mouse models, this work would likely have taken years and results would not necessarily be useful for humans.

 

The press release goes on to describe how Muotri and his team plan to push their preclinical studies using human stem-cell based models forward in hopes of entering clinical trials in the near future.

 

Related Links:

Multitasking molecule repairs damaged nerve cells, scientists discover in ‘stunning’ research breakthrough

/ cirmweb / 4 Comments

Every molecule in the body has a job to do—everything from maintaining healthy cell functions to removing dead or decaying cells requires a coordinated series of molecular switches to complete. There’s a lot we know about what these molecules do, but even more that we are still discovering.

The PSR-1 molecule, which normally clears out dead or dying nerve cells, has also been observed trying to repair them.

The PSR-1 molecule, which normally clears out dead or dying nerve cells, has also been observed trying to repair them.

And as reported in a pair of studies published this week in Nature and Nature Communications, a molecule that has long been known to clear out dying or damaged nerve cells also—amazingly—tries to heal them.

The molecule at the heart of these studies is called phophatidylserine receptor, or PSR-1 for short. PSR-1’s main job had been to target and remove cells that were dead or dying—a sort of cellular ‘cleanup crew.’

Some cells die because they’ve reached the end of their life cycle and are scheduled for destruction, a programmed cell death known as apoptosis. Other cells die because they have been damaged by disease or injury. In this study, scientists at the University of Colorado, Boulder and the University of Queensland (UQ) in Brisbane, Australia, discovered that not only does PSR-1 clear out dead cells, it tries to save the ones that haven’t quite kicked the bucket.

Specifically, the team observed PSR-1 literally reconnecting nerve fibers, known as axons, which had broken due to injury.

“I would call this an unexpected and somewhat stunning finding,” said one of the study’s lead authors Ding Xue in a news release. “This is the first time a molecule involved in apoptosis has been found to have the ability to repair severed axons, and we believe it has great therapeutic potential.”

Professor Ding Xue of the University of Colorado Boulder. [Credit: Casey A. Cass, University of Colorado]

Professor Ding Xue of the University of Colorado Boulder. [Credit: Casey A. Cass, University of Colorado]

Injuries to nerve cells that reside in the brain or spinal cord are particularly distressing because once damaged, the cells can’t be repaired. As a result, many research groups have looked to innovative ways of coaxing the cells to repair themselves. Xue and Hilliard see the potential of PSR-1 to be involved in such a strategy.

“This will open new avenues to try and exploit this knowledge in other systems closer to human physiology and hopefully move toward solving injuries,” said Hilliard.

The discovery of PSR-1’s role in axon repair is based off a key difference between cells undergoing programmed cell death and those that are dying due to injury.

During apoptosis, cells release a beacon to alert PSR-1 that they’re ready for removal. But when a nerve cell is injured, it sends out a distress signal. Explained Xue:

“The moment there is a cut to the nerve cell we see…a signal to PSR-1 molecules in the other part of the nerve that essentially says ‘I am in danger, come and save me.’”

While these experiments were performed in the model organism C. elegans (a small worm often used in this sort of research), the researchers are optimistic that a similar process is taking place in human nerve cells.

“Whether human PSR has the capacity to repair injured axons is still unknown. But I think our new research findings will spur a number of research groups to chase this question.”