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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>.
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<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

Early activation of certain cellular stress response pathways may help prevent the death of motor neurons in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) patients with FUS mutations, according to a recent study.
In particular, heat shock response (HSR) pathways and the integrated stress response (ISR) were increased in patient-derived motor neurons compared with cells from healthy people, and protected against toxic cellular stress caused by FUS protein clumps.
Still, these cells correspond to a relatively early stage of disease. Researchers believe these processes are likely to fail later on, contributing to neurodegeneration.
The study, &#8220;<a href="https://www.sciencedirect.com/science/article/pii/S2211124723000360">FUS ALS neurons activate major stress pathways and reduce translation as an early protective mechanism against neurodegeneration</a>,&#8221; was published in <a href="https://www.sciencedirect.com/journal/cell-reports">Cell Reports</a>.
About 5% of familial ALS cases are <a href="https://alsnewstoday.com/causes-of-als/">caused</a> by mutations in the FUS gene, which provides instructions for making a protein of the same name. Typically found in the cell nucleus, FUS plays various roles in regulating RNA metabolism and DNA repair. RNA is the intermediate molecule that guides the production of protein from a DNA template.
Some ALS-causing mutations in the FUS gene result in an abnormal FUS protein that, rather than going to the nucleus, accumulates in the cytoplasm — the fluid-filled space surrounding the nucleus — in motor nerve cells. This leads to toxic FUS clumps, or aggregates, forming.
These clumps can be particularly found inside <a href="https://alsnewstoday.com/news/stress-granules-ubiquitination-cell-damage/">stress granules</a> (SGs), small clumps comprised of proteins and RNA molecules that are temporarily formed in response to cellular stressors as a way to shut down certain cellular activities.
Research suggests the recruitment of mutant FUS to SGs is one process that underlies ALS. FUS aggregates appear to influence SG function, leading to a disrupted protein production balance (proteostasis) and increased cell death.
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<h3>Effect of FUS aggregates on stress granules</h3>
To better understand SG dynamics in FUS-associated ALS, researchers in Germany examined patient-derived motor neurons with FUS mutations that had been treated with certain molecules to induce cellular stress. These cells corresponded to relatively young cells that hadn&#8217;t been substantially impacted by neurodegeneration.
Results indicated a greater accumulation of FUS in the cytoplasm and a disruption of SG dynamics in the ALS motor neurons compared with healthy cells, particularly in response to stress.
&#8220;FUS neurons showed significantly more abundant and larger FUS-positive SGs,&#8221; the researchers wrote. Also, after a stressor, SGs were broken down more slowly in the FUS-ALS cells.
Certain cellular stress response pathways that&#8217;ve been implicated in regulating SG dynamics were activated in the FUS-ALS cells. Specifically, evidence suggested an increase of heat shock proteins (HSPs) and related molecules comprising the HSR in the ALS cells.
HSPs guide the proper folding of proteins and prevent their aggregation, but also regulate SG formation. HSR is normally activated in response to cellular stress to help maintain protein function and prevent cell death, but has shown to be diminished during neurodegeneration.
Inhibiting Hsp70, one of the main HSPs involved in that stress response pathway, led to a significant delay in breaking down stress granules. This was particularly pronounced in the patient-derived cells, resulting in an excessive accumulation of SGs.
The ISR pathway was also activated in mutant cells and was associated with decreased rates of translation, the process by which proteins are produced from an RNA template.
This process could &#8220;compensate for disturbed proteostasis by relieving the production of faulty protein species,&#8221; the researchers wrote. Interestingly, activating ISR also helped prevent mutant FUS levels from getting too high.
Further experiments showed HSR or ISR activation and the subsequent blockade of SG formation weren&#8217;t responsible for driving cellular death in the patient-derived cells. Instead, uncontrolled proteotoxicity — the accumulation of damaged or misfolded proteins under cellular stress — was the main driver of cell death in the early stages of FUS-ALS, according to the researchers. Thus, activation of ISR and HSR pathways appeared to be an early rescue mechanism to prevent this proteotoxicity.
&#8220;(Over)activation of stress response pathways in the mutant cells protects them from increased susceptibility to cell death early in the disease course even under proteotoxic overload and in spite of altered SG dynamics,&#8221; the researchers wrote. However, &#8220;it is likely that neurons lose the capability to upregulate HSP in response to FUS mutation with time, which may lead to a disrupted clearance of SG and FUS aggregation and a fatal decline of proteostasis&#8221; in the later disease stages, they said.
It&#8217;s likely that &#8220;the beneficial effect of ISR activation seen early in the FUS ALS pathology turns into a toxic mechanism over time,&#8221; they said, noting ISR inhibitors are being investigated for multiple neurodegenerative diseases. &#8220;The timing and duration of a potential [ISR inhibitor] treatment might be essential for observing preventive outcomes.&#8221;

Tag: FUS-associated ALS

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

Early stress pathway activation combats cell death in FUS-ALS