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Storing chemicals such as gasoline, lawn care products, and paints in a garage attached to a home was associated with an increased risk of <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in a recent analysis.
Researchers believe the findings add to knowledge about environmental exposures — workplace, recreational, or residential — that contribute to the risk and progression of the neurodegenerative disease. Such exposures are collectively known as the “ALS exposome.”
“With each study, we better understand the types of exposures that increase the risk of developing ALS,” Eva Feldman, MD, PhD, professor and director of the ALS Center of Excellence at the University of Michigan, and a senior author, said in a <a href="https://www.michiganmedicine.org/health-lab/chemicals-stored-home-garages-linked-als-risk">university news release</a>. “We now need to build on these discoveries to understand how these exposures increase ALS risk.&#8221;
The study, “<a href="https://pubmed.ncbi.nlm.nih.gov/38557405/">Residential exposure associations with ALS risk, survival, and phenotype: a Michigan-based case-control study</a>,&#8221; was published in Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration.
Exposure to certain environmental toxins, especially pesticides and heavy metals, has been strongly linked to an increased risk of <a href="https://alsnewstoday.com/causes-of-als/">developing ALS</a>.
Feldman and her colleagues have shown that people with ALS have <a href="https://alsnewstoday.com/news/pesticide-exposure-may-als-risk-factor/">higher concentrations of organic pollutants</a>, especially pesticides, in their blood than people without ALS and that such pollutants were associated with <a href="https://alsnewstoday.com/news/exposure-to-environmental-pollution-reduces-survival-rates-of-als-patients-study-reports/">worse survival outcomes</a>. Lifetime exposure to these factors might <a href="https://alsnewstoday.com/news/environmental-pollutants-blood-linked-als-risk-survival-odds/">predict a person’s risk</a> of developing the neurodegenerative disease, they&#8217;ve shown.
While many elements of the ALS exposome come from the workplace, certain <a href="https://alsnewstoday.com/news/taking-part-recreational-activities-may-increase-als-risk-study/">recreational activities</a> like woodworking or gardening, where volatile chemicals may be used, have also recently been linked to ALS.
[recommended-reading id=87815]
<h3>Link between ALS, home-based exposures</h3>
Here, the scientists looked at the possible contributions of home-based exposures, given that gasoline, solvents, cleaners, and paints are routinely found at home, especially in the garage.
They sent a survey to more than 600 people, including 367 ALS patients seen at the university’s clinic and 255 people without ALS from the local community, who served as a control group. The participants were asked about their current and previous home environments.
Among the top residential factors associated with an elevated ALS risk was storing chemicals in a garage attached to the house. These included fuels such as gasoline and kerosene, gasoline-powered equipment, lawn care products, pesticides, paint, solvents, woodworking supplies, and bleach, with each raising the odds of developing ALS by anywhere from 9% to 16% with every five years of additional exposure.
Storing these items was also associated with a risk of ALS when they were kept in a garage detached from the home, although the links were slightly weaker.
Researchers believe this makes sense given the flow of air into living spaces through an entry door and small openings in walls and floors.
Other residential factors linked to ALS risk included having a humidifier in the home, central heating systems that used oil as fuel, and having a pet dog, which might &#8220;expose residents to pesticides used to control fleas, ticks and other vectors.&#8221; The researchers said a humidifier could be &#8220;associated with microbial contamination or biocides.&#8221;
None of the identified factors were significantly associated with ALS survival, but having pesticides, lawn care products, and woodworking supplies in the home was close to being significant.
Many of the chemicals in the analysis have toxic components and most have been linked to ALS in other studies, especially as they related to occupational exposures, the researchers said.
“Our findings are very consistent with the literature, but … are highly significant in extending the literature by showing that such exposures in residential settings have a meaningful impact on ALS risk,” wrote the researchers, who said their finding that woodworking supplies are associated with ALS are consistent with a recent study where woodworking as a hobby was associated with the neurodegenerative disease.
Stephen Goutman, MD, of the University of Michigan and the study’s first author, said more research is needed to determine whether it&#8217;s the “activities that associate with ALS risk or the exposures to related products.”
The analysis had some limitations, including that the respondents may not accurately recall environmental exposures from prior living spaces and not all types of exposures were covered in the survey. Still, the analysis provides insights into the home-based factors that may contribute to the disease.
“Identifying disease-provoking exposures can inform and motivate interventions to reduce exposure, risk and, ultimately, the ALS burden,” Goutman said. “Exposures in the home setting are an important part of the ALS exposome, as it is one place where behavior modifications could possibly lessen ALS risk.”

Environmental exposure to home chemicals tied to increased ALS risk

In people who experience a traumatic brain injury, or TBI — which is linked to a greater likelihood of developing <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — blocking the activity of a protein called KCNJ2 may lower the risk of ALS, according to new research done in lab models.
“Targeting KCNJ2 may reduce the death of nerve cells after TBI,&#8221; Justin Ichida, PhD, a professor at the University of Southern California and the study&#8217;s co-author, said in a <a href="https://www.eurekalert.org/news-releases/1039536">press release</a>.
&#8220;This could have potential as either a post-injury treatment or as a prophylactic for athletes and others at high risk for TBI,&#8221; said Ichida, also a principal investigator at the Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC.
In their study, the researchers presented a lab model — &#8220;a human organoid platform for the discovery and validation of modifiers of &#8230; injury&#8221; — that aims to help in the development of novel treatments for people who experience a TBI.
Titled &#8220;<a href="https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(24)00085-7">KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury</a>,&#8221; the study was published in Cell Stem Cell.
[recommended-reading id=72027]
<h3>Researchers seek to bridge gap from rodent to human models</h3>
A history of traumatic brain injury is one of the strongest <a href="https://alsnewstoday.com/causes-of-als/">risk factors for ALS</a> and other neurodegenerative diseases. Presumably, injury to the brain causes changes in brain cells that set the stage for further disease. However, the specific mechanisms are not fully understood, and most of what is known has been deduced from experiments in mice.
&#8220;Although current TBI models — predominantly rodent-focused — have been instrumental in gaining insights into neurodegenerative mechanisms, efforts to develop effective human-relevant therapeutic strategies have been limited,&#8221; the researchers wrote.
To gain greater insight, and potentially find strategies to mitigate these mechanisms, a team of scientists, mostly from the Keck School of Medicine at USC, conducted a series of experiments using patient-derived brain organoids.
Organoids are a type of lab model in which cells are grown in a three-dimensional structure that more closely mimics the architecture of cells in the body, rather than growing the cells in a dish as is traditionally done in lab experiments. This model has the advantage of using human cells, complementing previous work in mice.
To study the effects of physical injury to these cells, the researchers devised a system where they damaged organoids using high-frequency sound waves.
&#8220;Our mechanical injury model represents a starting point for bridging the translational gap from rodent to human models of TBI,&#8221; the researchers wrote.
In an initial battery of tests, the researchers demonstrated that cells in this model show many of the same molecular changes that have previously been reported in mice. Among the notable molecular changes, a protein called TDP-43 formed abnormal clumps in damaged neurons. Similar clumps of the TDP-43 protein are a hallmark of ALS.
The scientists further showed that cell survival was improved when the organoids were treated with a chemical to reduce abnormal TDP-43 accumulation. This illustrates &#8220;that TDP-43 dysfunction is a major driver of injury-induced neuronal death in organoids,&#8221; they wrote.
These results &#8220;suggest that targeting TDP-43 may be important for mitigating neuronal injury and death after TBI,&#8221; the scientists added.
[recommended-reading id=86531]
<h3>Higher levels of KCNJ2 protein linked to risk of ALS</h3>
When the researchers performed similar experiments using organoids derived from people with an ALS-causing mutation in the C9ORF72 gene, there was substantially more abnormal TDP-43 accumulation than was seen in organoids from people without the disease.
&#8220;Together, these data show that C9ORF72 [ALS] patient organoids have enhanced susceptibility to TDP-43 loss of function following &#8230; injury, which may lower the threshold for disease,&#8221; the researchers wrote.
&#8220;These findings highlight TDP-43 dysfunction as a potential mechanistic link to explain how TBI and genetic mutations can synergize to increase the risk of long-term neurodegenerative diseases,&#8221; they added.
In their experiments, the researchers noticed that organoids carrying an ALS-causing mutation tended to express higher levels of a protein called KCNJ2. When they treated organoids with a chemical to block this protein shortly after inducing injury, the cells had better survival with fewer abnormal TDP-43 aggregates.
[quote=&#8221;center&#8221;]We found that small molecule inhibition of KCNJ2 [one hour] post-injury was sufficient to improve neuronal [nerve cell] survival.[/quote]
Further experiments in mouse models consistently showed that blocking KCNJ2 reduced damage to neurons following brain injury.
&#8220;We found that small molecule inhibition of KCNJ2 [one hour] post-injury was sufficient to improve neuronal survival,&#8221; the scientists wrote.
This finding implies that blocking KCNJ2 could be a useful prophylactic or preventive treatment to reduce the risk of future neurological disorders in people with TBI, the scientists noted.
The team stressed that further work is needed to verify these findings and figure out how to apply them in clinical settings. However, according to the researchers, such preventive treatments might be especially useful for people at a high risk of traumatic brain injuries, such as athletes who play rough contact sports.

Blocking KCNJ2 protein may reduce risk of ALS after brain injury: Study

People with negative responses to a tuberculin skin test a few years after being vaccinated against tuberculosis had a significant, 25% lower risk of developing <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) in their lifetime, according to a study in Norway.
Because a positive reaction is linked to the recruitment of T cells — a type of immune cell involved in memory immunity and responses to vaccines — these findings may support the role of T-cell responses in the development of ALS, its researchers said.
The study, “<a href="https://www.sciencedirect.com/science/article/pii/S2666354623001187">Tuberculin responses after BCG vaccination predict amyotrophic lateral sclerosis risk</a>,” was published in the journal <a href="https://www.sciencedirect.com/journal/brain-behavior-and-immunity-health">Brain, Behavior, &amp; Immunity – Health</a>.
[recommended-reading id=88406]
<h3>Immune system response to motor neuron damage known in ALS</h3>
In people with ALS, inflammatory cells such as T-cells and microglia are known to locate in brain and spinal cord regions where motor neurons are damaged. However, it remains unknown if this immune cell infiltration is an actual contributor to disease onset and progression, or if it is a consequence of other disease processes.
“If T cells play a primary role, one would expect to find evidence of altered regulation of T cell responses before ALS development,” the researchers wrote.
To better understand T-cells&#8217; role in ALS, researchers at the University of Oslo and Akershus University Hospital used data from a compulsory screening program of people in a Bacillus Calmette–Guerin (BCG) vaccine drive to prevent tuberculosis. Tuberculosis is an infectious disease caused by the Mycobacterium tuberculosis bacteria that mainly affects the lungs.
Individuals were monitored regularly to determine if they had a positive immunological response to the vaccination and remained protected from tuberculosis, which was widespread in Norway in the early 20th century.
Monitoring was done using the tuberculin skin test, or TST, in which a small amount of tuberculin — a protein from the bacteria that causes tuberculosis — is injected into the skin. The skin reaction was evaluated for size, hard area, or swelling after a few days.
Usually, BCG vaccination results in a positive TST test, but some vaccinated people fail to develop an immune response against tuberculin, meaning their immune system is not equipped to fight the tuberculosis bacteria in case of an infection.
While seemingly unrelated, immune mechanisms involved in a TST response are relevant to ALS because both involve the recruitment of T-cells, enabling researchers to compare T-cell responses in people who later ended up developing ALS with those who didn&#8217;t.
From the screening program data, the scientists identified nearly 325,000 people, born between 1910 and 1955, who received a BCG vaccination and had a TST examination one to 15 years afterwards.
Over a median of 40 years of follow-up, 496 of them developed ALS.
<h3>Negative skin test results indicate a weaker adaptive immune response</h3>
People with a negative TST result had a 25% lower risk of ALS, compared with those with a positive TST reaction, results showed. This association was observed throughout the follow-up, and it was still present four decades later.
Notably, the association between a negative TST test result and reduced ALS risk was even greater as the time between vaccination and TST decreased. For example, patients with a negative TST result within 10 years of vaccination were 33% less likely to develop the disease, and those with a negative test within five years of getting the vaccine were 43% less likely.
In a subgroup of 228,900 people who were vaccinated during adolescence (ages 12 to 17), researchers identified 275 cases of ALS over a median follow-up of 43 years. Regardless of the interval between vaccination and screening, patients in this group with a negative TST reaction had a 33% lower risk of developing ALS.
“We conclude that on population level, a weak secondary adaptive immune response, as measured by TST following BCG vaccination, is associated with low ALS risk several decades later. These results support a primary role for immune regulation in ALS development,” the researchers wrote.
The inability to exclude possible confounding factors that could impact the risk for ALS was noted as a study limitation.

Tuberculosis vaccine screening links T-cell response to ALS risk

A new genetic risk score that takes hundreds of different genetic variations into account may help predict who&#8217;s most likely to develop <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS).
The score needs to be validated in future studies before being used in the clinic, but could be important to stratify people according to their risk of developing the disease and aid in designing ALS prevention studies.
&#8220;This polygenic [multi-gene] scoring system we developed for ALS allows us to better understand the genetic architecture of the disease. This may help to distinguish which populations have greater odds to develop the disease and inform future prevention studies and interventions,&#8221; Stephen Goutman, MD, co-author of the study from the University of Michigan, said in a <a href="https://www.eurekalert.org/news-releases/993221">press release</a>.
The study, &#8220;<a href="https://ng.neurology.org/content/9/4/e200079">Cumulative Genetic Score and C9orf72 Repeat Status Independently Contribute to Amyotrophic Lateral Sclerosis Risk in 2 Case-Control Studies</a>,&#8221; was published in <a href="https://ng.neurology.org/">Neurology Genetics</a>.
The <a href="https://alsnewstoday.com/causes-of-als/">causes of ALS</a> remain poorly understood. Genetics are thought to play a role and mutations in a few key genes have been shown to cause a minority of cases. Most people with ALS don&#8217;t have mutations in any of these genes, even in many cases where the disease <a href="https://alsnewstoday.com/forms-of-als-familial-als/">runs in families</a> and is presumed to have a strong genetic component, however.
Rather than looking at the effect of mutations in individual genes, the researchers here developed a scoring system that accounts for many different genetic variations cumulatively. &#8220;It is increasingly clear that many common [genetic variations] may contribute a small amount of disease risk,&#8221; they wrote.
[recommended-reading id=80074]
<h3>Assessing ALS risk</h3>
The scoring system was derived from an earlier genome-wise association study (GWAS) that included more than 20,000 people with ALS, along with nearly 60,000 people without it. A GWAS is a type of analysis to identify genetic variations that are statistically more common among people with a disease, which implies these variations might affect the risk of developing it.
The system took into account 275 ALS-associated single-nucleotide variations (SNVs), or places where one nucleotide (a building block of DNA) differs from person to person. The score excludes variations in or near the C9ORF72 gene, the most common single-gene cause of ALS.
Many of the 275 SNVs in this score are located in genes important for nerve cells&#8217; health and function, noted the researchers, who calculated risk scores for 219 people with ALS, 7.8% of whom had a family history of the disease. Scores were also calculated for 223 people without ALS or a family history of the disease for comparison.
Using statistical analyses, the researchers evaluated whether the scores were significantly higher among people with ALS and found they were. For every one standard deviation increase in risk score, the likelihood of ALS was increased by about 28%.
Based on the models, the researchers estimated that, if a theoretical treatment were available that could completely eliminate the increased risk associated with these 275 genes, about 4.1% of cases wouldn&#8217;t have developed.
&#8220;Currently, there is no biomarker or tool that can definitively predict who will develop ALS later in life. Therefore, even if the polygenic score can only explain a small number of individuals at risk, it could be an important screening method for risk reduction,&#8221; the researchers wrote.
Findings from the initial analyses were replicated using data from a Spanish group of 548 ALS cases and 2,756 people without the disease. Because not all SNVs were available in this dataset, the analysis focused only on the 132 SNVs with available data. Nonetheless, the results in the Spanish cohort showed the risk of ALS was significantly increased among those with a higher genetic risk score, consistent with the results from the original analysis.
&#8220;Although the SNVs included in the polygenic score were adjusted due to the available overlap of SNVs in both data sets, there was consistency in the magnitude of the polygenic score effect, further providing support for our proposed polygenic score. Replication of polygenic scores is critical to ascertain that the methods and population background used to develop the score is generalizable,&#8221; wrote the researchers, who emphasized that further research that looked at at more SNVs in larger sample sizes was needed to verify the results and refine the genetic risk score. Diverse populations should be included to make the findings as generalizable as possible, they said.
&#8220;There is a lot of room for improvement in ALS prediction so that folks at risk can be identified for prevention and treatment. Future research into additional risk factors, including environmental exposures, will be critical,&#8221; said Kelly M. Bakulski, PhD, study co-author and professor of epidemiology at the University of Michigan.

Polygenic scoring system may help to predict ALS risk

Allopurinol and carvedilol, two medications respectively used to manage gout and high blood pressure, significantly reduce the chances of developing <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), <a href="https://alzheimersnewstoday.com/what-is-alzheimers-disease/">Alzheimer&#8217;s</a>, or <a href="https://parkinsonsnewstoday.com/what-is-parkinsons-disease/">Parkinson&#8217;s disease</a>, a new study suggests.
&#8220;These findings suggest a possible new direction for repurposing or developing medications for neuroprotection,&#8221; Brad Racette, MD, study co-author at Barrow Neurological Institute, said in a <a href="https://www.barrowneuro.org/about/news-and-articles/press-releases/study-common-gout-medication-reduces-risk-of-alzheimers-parkinsons-als/">press release</a>.
The study, &#8220;<a href="https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0285011">Biologic targets of prescription medications and risk of neurodegenerative disease in United States Medicare beneficiaries</a>,&#8221; was published in <a href="https://journals.plos.org/plosone/">PLOS One</a>.
[recommended-reading id=82906]
ALS, Parkinson&#8217;s, and Alzheimer&#8217;s are all diseases marked by the gradual death and dysfunction of nerve cells in the brain and/or spinal cord. The specific manifestations of these three diseases differ, and their exact <a href="https://alsnewstoday.com/causes-of-als/">causes</a> remain largely unknown. Nonetheless, it&#8217;s thought that some biological mechanisms — such as increased inflammation and cellular stressors — likely play a role in driving all of these conditions.
Here, scientists at Barrow, the Washington University School of Medicine in St. Louis, and University of Witwatersrand in Johannesburg conducted an analysis using data collected by Medicare, the U.S. government program that provides health insurance to people 65 and older, aiming to identify medications that might alter the risk of these diseases.
For the analysis, researchers looked at medications prescribed in 2006-2007, and then identified patients diagnosed with one of the three diseases in 2009.
The analysis included data on more than 370,000 people. Among them, 1,341 had ALS only, 8,332 had Alzheimer&#8217;s only, 28,679 had Parkinson&#8217;s, and 4,533 had a combination of at least two of the neurodegenerative conditions. There also were 334,387 people with comparable demographic characteristics who didn&#8217;t develop any of these diseases.
Most patients in the analysis were white, and all were older than 65. A follow-up analysis using data from 2010-2014 also was conducted to verify the results.
&#8220;In this large, population-based study, we took a unique approach to investigate the association between various medication categories in relation to the three most common neurodegenerative diseases: Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis,&#8221; said Racette, chairman of neurology and senior vice president at Barrow.
<h3>Likelihood of developing ALS, Parkinson&#8217;s, Alzheimer&#8217;s reduced in statistical models</h3>
Statistical models showed the chances of developing any of these three diseases was significantly reduced among patients who had been treated with allopurinol, which is commonly given to manage gout (a form of inflammatory arthritis characterized by joint swelling and pain). For ALS specifically, results indicated the likelihood was reduced by 13%.
The reduction was estimated at 16% for Parkinson&#8217;s and 31% for Alzheimer&#8217;s. Considering all three diseases collectively, the likelihood was reduced by 34% among patients on allopurinol.
Allopurinol works by blocking the activity of an enzyme called xanthine dehydrogenase, which reduces the production of a waste product called uric acid that drives inflammation in gout.
Results showed that another medication, carvedilol — which is used to manage blood pressure and heart disease, and can also reduce activity of the xanthine dehydrogenase pathway — also was associated with a reduced risk of these three diseases.
In particular, people taking this medication were 22% less likely to develop ALS, and the changes of having Parkinson&#8217;s or Alzheimer&#8217;s were reduced by 10%-19%. Overall, the chances of developing any of these conditions were 28% lower.
Other gout and blood pressure medications that don&#8217;t act on this pathway did not show a consistent relationship with disease risk. Collectively these findings suggest these two medications may be repurposed to prevent these conditions.
The team noted the analysis was limited by its use of insurance data from elderly patients, so the findings may not be applicable to younger populations. They also emphasized it&#8217;s impossible to draw definitive conclusions about cause and effect from these data, urging further study to investigate whether these treatments can actually reduce disease risk or whether other factors might explain these associations.
&#8220;Ultimately, further experimental and epidemiologic studies will be required to understand whether our findings are causal and related,&#8221; they wrote.
The scientists also stressed this study was assessing whether these medications affect the risk of developing these diseases, not whether the medications might change the course of the disease for people who already have it.
“The medication associations we studied relate to disease risk. Further research will be necessary to examine whether this mechanism slows progression of these diseases,&#8221; Racette said.

Gout medication decreases risk of ALS and other diseases: Study

A potential new genetic risk factor for <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) has been discovered by researchers at the University of Washington.
The scientists say a mutation in which a region of the WDR7 gene is repeated more times than usual may increase the risk of ALS.
“We believe that this expansion acts as a genetic modifier to disease susceptibility, as in the repeat on its own doesn’t cause disease, but it functions in conjunction with other genetic risk factors,” Samuel Smukowski, a graduate student at the University of Washington, said in a talk at the Muscular Dystrophy Association&#8217;s MDA Clinical &amp; Scientific Conference, held in Texas and virtually March 19 through 22.
Smukowski’s talk was titled “<a href="https://www.mdaconference.org/abstract-library/functional-consequences-of-a-human-specific-tandem-repeat-in-wdr7-associated-with-als/">Functional consequences of a human-specific tandem repeat in WDR7 associated with ALS</a>.”
[recommended-reading id=82805]
<h3>More than 50 VNTR expansions have been linked to neurological diseases</h3>
The human genome contains instructions for making all of the proteins needed for the body to function. Within the genome, there are many areas called variable number tandem repeats, or VNTRs, where a particular sequence of nucleotides (the building blocks of DNA) gets repeated over and over.
A VNTR expansion is a type of mutation where a VNTR sequence has many more repeats than normal. More than 50 VNTR expansions have been linked to neurological diseases, and a mutation of this type in the gene C9ORF72 is the most common <a href="https://alsnewstoday.com/als-and-genetics/">ALS-associated mutation</a>.
Smukowski and his colleagues initially assessed data from a family affected by <a href="https://alsnewstoday.com/forms-of-als/familial-als/">familial ALS</a>. Using cutting-edge genetic sequencing technology, the team discovered a previously unreported 69-nucleotide-long VNTR sequence in the gene WDR7.
A VNTR expansion in this gene, which provides instructions for making a protein that’s involved in the function of synapses (the connections between nerve cells), appeared to be associated with ALS in the family.
Analyses of data from more than 900 people in three groups of <a href="https://alsnewstoday.com/forms-of-als-2/sporadic-als/">sporadic ALS</a> patients — one from the Answer ALS program, one from Quebec, and a third from the Coriell Institute for Medical Research — showed that ALS patients more commonly had an expanded VNTR region in the WDR7 gene compared with people who did not have ALS.
&#8220;ALS patients disproportionately have longer repeat expansions,&#8221; Smukowski said.
[quote=&#8221;center&#8221;]We believe that this expansion acts as a genetic modifier to disease susceptibility, as in the repeat on its own doesn’t cause disease, but it functions in conjunction with other genetic risk factors.[/quote]
When WDR7 and other protein-coding genes are &#8220;read&#8221; to produce a protein, the genetic code is copied over into a temporary molecule called messenger RNA (mRNA). Some ALS-associated mutations are known to cause mRNA and proteins to clump up inside cells, which is thought to be toxic and contribute to the nerve cell degeneration that drives ALS.
The researchers showed that mRNA from the WDR7 gene harboring an expansion in the VNTR region was found in clumps alongside the ALS-linked protein TDP-43.
The team also showed that the repeat region could be used by cells to produce microRNAs, which are regulatory RNA molecules that bind to the mRNAs of certain proteins to reduce their levels. The larger the expansion in the WDR7 VNTR region, the more microRNAs were produced, the research showed.
In theory, this could mean that the VNTR expansion could change the levels of specific proteins in cells, ultimately dysregulating cellular activity.
[recommended-reading id=82220]
Smukowski noted that several of the genes known to be regulated by these microRNAs have important roles in neurological function, with mutations in one gene, called VPS53, having been shown to spontaneously lead to ALS in mice.
&#8220;Therefore it’s possible that a high copy number of this repeat expansion is interfering with these target genes’ normal expression,&#8221; he said.
“Our findings underscore the biological impact of tandem repeat expansions in modulating susceptibility to ALS,” the scientists wrote in their abstract.
They are continuing work to understand how this WDR7 mutation, and other VNTR expansions, may affect the development and progression of ALS.

Tag: ALS risk

Environmental exposure to home chemicals tied to increased ALS risk

Blocking KCNJ2 protein may reduce risk of ALS after brain injury: Study

Tuberculosis vaccine screening links T-cell response to ALS risk

Polygenic scoring system may help to predict ALS risk

Gout medication decreases risk of ALS and other diseases: Study

MDA 2023: Expansion in WDR7 gene linked to increased ALS risk