A SUPER-powered WP Engine Atlas Test Site

Joe&#039;s Atlas Experimentation Site

People with <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) due to mutations in the FUS gene may benefit from interferon-gamma treatment to delay disease onset and/or progression, an early preclinical study suggests.
Researchers found that an immune signaling protein called interferon (INF)-gamma protected patient-derived motor neurons from oxidative stress.
INF-gamma also restored the activity of genes that normally respond to oxidative stress, a type of cellular damage implicated in the disease, and improved overall protein production within motor neurons, which is compromised in FUS-related ALS.
The cell-based study, “<a href="https://onlinelibrary.wiley.com/doi/10.1111/bpa.13206">IFNγ protects motor neurons from oxidative stress via enhanced global protein synthesis in FUS-associated amyotrophic lateral sclerosis</a>,” was published in the journal <a href="https://onlinelibrary.wiley.com/journal/17503639">Brain Pathology</a>.
[recommended-reading id=86997]
<h3>FUS gene mutations account for 5% of familial ALS, 1% of sporadic cases</h3>
<a href="https://alsnewstoday.com/als-and-genetics/">Mutations in the FUS gene</a>, which encodes a protein of the same name, cause about 5% of <a href="https://alsnewstoday.com/forms-of-als-familial-als/">familial ALS</a> and about 1% of <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a> cases. FUS mutations have been associated with the most aggressive forms of ALS, including a type that occurs in adolescents and young adults.
FUS protein is typically found in the cell nucleus and plays various roles in protein production. However, exactly how these mutations cause the death of motor neurons, the nerve cells that control voluntary movements, which lead to <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptoms</a>, is still unclear.
To reveal biological defects caused by FUS mutations, scientists in the Netherlands and Brazil generated motor neurons derived from ALS patients who carried FUS-R521H, a prominent ALS mutation. Control cells were derived from family members who did not have ALS.
Results showed that cell viability, or the proportion of healthy cells, was similar between the control and FUS-ALS motor neurons. However, when exposed to sodium arsenite, a well-known inducer of oxidative stress, mutant cells were significantly less viable than controls.
<h3>FUS-ALS motor neurons more sensitive to oxidative stress</h3>
FUS-ALS motor neurons were “more sensitive to oxidative stress,” the scientists noted.
Gene activity experiments revealed oxidative stress sensitivity of motor neurons might be explained by changes in genes related to the immune system and two major signaling pathways: TGF-beta and mTORC, both essential for proper cell function.
Consistent with TGF-beta’s role in the production of immune signaling proteins called cytokines, FUS-ALS motor neurons, when exposed to sodium arsenite, produced more interleukin-8 and CCL2 cytokines and less INF-gamma and interleukin-15. In control cells, INF-gamma increased with sodium arsenite exposure, something that FUS-ALS cells failed to do, the team noted.
Because mTORC and FUS both have known roles in protein production, the researchers also measured the rates of protein synthesis. Overall, FUS-ALS motor neurons had lower rates than control cells, but no differences were noticeable in gene activity, which was “in agreement with findings of others.”
Significantly decreased protein production rates were also found in healthy cells engineered to overproduce FUS-R521H. This suggested that the FUS mutation resulted in an overly-active FUS protein in ALS motor neurons, rather than in reduced levels of FUS.
[quote=&#8221;center&#8221;]Our findings suggest that early-diagnosed [FUS-ALS] patients might benefit from [INF-gamma] treatment to slow down disease progression.[/quote]
<h3>ALS motor neurons more susceptible to cell death</h3>
ALS motor neurons are “more susceptible to apoptosis [cell death] due to decreased protein synthesis rates caused by an R521H gain-of-function [overactive] mutation in the FUS gene,” the researchers wrote.
In healthy cells, FUS is known to move between the cell nucleus and the cytoplasm (the gelatinous liquid that fills the inside of a cell). In ALS, however, FUS is mainly found in the cytoplasm of motor neurons, which ultimately leads to FUS clumping.
Consistently, in FUS-ALS motor neurons, FUS levels were reduced in the nucleus and increased in the cytoplasm. Protein interaction studies showed that, when in the cytoplasm, FUS-R521H binds to various proteins that initiate protein synthesis.
The abnormal localization of FUS-R521H was also found in cells harboring mutations that cause other forms of ALS.
“These findings suggest that aberrant cytoplasmic localization of FUS is common among ALS subtypes,” the scientists wrote, and “leads to promiscuous binding of FUS to cytoplasmic proteins with a role in [protein production].”
[recommended-reading id=21684]
<h3>INF-gamma treatment decreased cell death to control levels</h3>
Finally, treatment with INF-gamma, which was reduced in FUS-ALS motor neurons, increased mutant cell viability after sodium arsenite exposure and decreased cell death to control levels. INF-gamma treatment also rescued the impaired gene activity seen in response to oxidative stress.
Although the treatment did not affect protein synthesis rates in control cells, it significantly increased them in FUS-ALS motor neurons, with or without sodium arsenite exposure.
INF-gamma treatment also increased FUS levels in the nucleus, almost to those in control cells. In agreement, suppressing levels of FUS improved protein synthesis rates in FUS-R521H cells and reduced cell death, similar to INF-gamma.
“While further work is required to understand how [INF-gamma] restores FUS localization and impaired translation rates, our findings suggest that early-diagnosed [FUS-ALS] patients might benefit from [INF-gamma] treatment to slow down disease progression,” the researchers concluded.

Interferon-gamma therapy may help delay familial ALS: Cell study

Dimethyl fumarate (DMF) — an oral medication approved for <a href="https://multiplesclerosisnewstoday.com/multiple-sclerosis-overview/">multiple sclerosis</a> — and H-151, an experimental treatment, can suppress inflammatory and abnormal immune pathways thought to be involved in <a href="https://alsnewstoday.com/sporadic-als/">sporadic amyotrophic lateral sclerosis</a> (ALS).
These are the findings of a study using immune cells from sporadic ALS patients that also showed DMF worked better when given in combination with epoxyeicosatrienoic acids (EETs), signaling fatty molecules that can be found in certain foods.
The results suggest DMF, in combination with a diet rich in certain fatty molecules, and H-151 could be therapeutic candidates for sporadic ALS patients not responding to currently available therapies, according to a research team led by scientists at the University of California, Los Angeles (UCLA).
[recommended-reading id=85260]
<h3>Researchers plan to file application to test medications in clinical trial</h3>
With these preclinical data, the researchers plan to file an application to test the medications in a clinical trial, according to a <a href="https://www.uclahealth.org/news/researchers-report-advance-immune-therapy-against-als">UCLA press release</a>. But before moving to clinical testing, they’ll do more research on immune cells of more patients.
The study, “<a href="https://faseb.onlinelibrary.wiley.com/doi/10.1096/fj.202300573R">Therapy of autoimmune inflammation in sporadic amyotrophic lateral sclerosis: Dimethyl fumarate and H-151 downregulate inflammatory cytokines in the cGAS-STING pathway</a>,” was published in the <a href="https://faseb.onlinelibrary.wiley.com/journal/15306860">FASEB Journal</a>.
ALS is a progressive neurodegenerative disease that affects motor neurons, the specialized nerve cells that control voluntary movement, in the brain and spinal cord. Motor neuron damage and death result in muscle weakness, breathing difficulties, and <a href="https://alsnewstoday.com/symptoms-of-als/">other symptoms</a> that worsen over time.
While the exact <a href="https://alsnewstoday.com/causes-of-als/">causes of ALS</a> remain largely unclear, they are thought to involve a combination of genetic and environmental factors. In sporadic ALS, the most common and non-inherited form of the disease, evidence suggests the involvement of inflammation and autoimmunity, or abnormal immune attacks against the body’s own healthy molecules.
The UCLA team, along with a colleague at Saint John&#8217;s Cancer Institute, in California, first set out to assess exactly what immune cells are involved in sporadic ALS and how they behave over the course of the disease.
By analyzing spinal cord samples from a 68-year-old man with sporadic ALS, the researchers showed that the spinal cord was invaded by cytotoxic T-cells, a type of immune cell that can kill microbes and certain cells.
These cells tested positive for interleukin (IL)-17A, a pro-inflammatory molecule, and granzyme B, an enzyme that can trigger nerve cell death and long-lasting inflammation.
[quote=&#8221;center&#8221;]Future investigation and eventually clinical trials need to determine whether the combination of H-151 with DMF would be synergistic against autoimmune inflammation in [sporadic ALS] patients.[/quote]
<h3>Study analyzed immune cells from 8 men with sporadic ALS, 4 healthy people</h3>
Given that immune cells travel from the blood to tissues throughout the body, the researchers analyzed the gene activity profile of immune cells in blood samples from eight men with sporadic ALS and four healthy people (three women and one man).
In the early stages of disease, genes coding for the pro-inflammatory molecules IL-12A, IFN-gamma, and TNF-alpha, as well as granzymes, were more active in patients than in healthy controls.
Later on, at more advanced stages of disease, immune cells turned on genes coding for IL-17B, a signaling molecule involved in autoimmune reactions, as well as two chemokines called CXCL9 and CXCL10. Chemokines can attract immune cells, including cytotoxic T-cells, into the brain and spinal cord.
In turn, genes coding for the anti-inflammatory molecules IL-10 and TGF-beta became less active over the course of the disease.
The researchers then tested whether certain medications — DMF and H-151 — could tone down these inflammatory and autoimmune signals linked to sporadic ALS.
Sold as <a href="https://multiplesclerosisnewstoday.com/tecfidera-dimethyl-fumarate-multiple-sclerosis/">Tecfidera</a> by <a href="https://www.biogen.com">Biogen</a> and also available as generic versions, DMF is an oral small molecule approved for treating multiple sclerosis and psoriasis, two autoimmune conditions. It works by reducing inflammation and modulating immune system activity.
H-151, an experimental treatment, can decrease the production of pro-inflammatory molecules by lab-grown immune cells. It suppresses a signaling pathway called cGAS/STING, which is involved in immune cell activation.
Lab-grown immune cells from two sporadic ALS patients, a 40-year-old man and a 65-year-old woman, were exposed to either DMF alone or in combination with EETs, or H-151.
EETs are a type of fatty molecule with anti-inflammatory effects that are derived from arachidonic acid, a polyunsaturated fatty acid (PUFA). PUFAs are generally considered good fats, being found in fatty fish, such as salmon and mackerel, seafood, nuts, and certain seeds.
Results showed that both DMF and H-151 reduced the activity of genes coding for granzymes and pro-inflammatory molecules, such as IL-6, IL-15, and IFN-gamma. The effect of DMF was even greater when combined with EETs.
[recommended-reading id=21684]
<h3>Both medications suppressed inflammatory, autoimmune signaling in cells</h3>
These findings indicate that both medications suppressed “inflammatory and autoimmune signaling” in immune cells from sporadic ALS patients, the team wrote, supporting “their investigation in a clinical trial.”
The researchers noted that DMF has been previously tested in an ALS clinical trial, in combination with the standard treatment riluzole (sold as <a href="https://alsnewstoday.com/rilutek-riluzole-for-als/">Rilutek</a>, <a href="https://alsnewstoday.com/exservan-riluzole-oral-film/">Exservan</a>, and <a href="https://alsnewstoday.com/tiglutik-riluzole-oral-suspension/">Tiglutik</a>). Results showed that while the combination treatment was generally safe, it did not result in significant benefits in terms of ALS progression.
The current study’s results “suggest that DMF may be effective when combined with a diet rich in certain polyunsaturated fatty acids,” the team wrote.
“Future investigation and eventually clinical trials need to determine whether the combination of H-151 with DMF would be synergistic against autoimmune inflammation in [sporadic ALS] patients,” the researchers wrote. A synergy occurs when the combined effect of two medications is greater than the sum of their separate effects.

Tag: cell study

Interferon-gamma therapy may help delay familial ALS: Cell study

Study uncovers 2 therapies to help target autoimmune inflammation