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Increased accumulation of p62, a protein involved in a cellular recycling process called autophagy, in the spinal cord is associated with worse survival outcomes in people with sporadic <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS), a study revealed.
Autophagy is the cellular process responsible for breaking down proteins and other complex molecules that are abnormal or no longer needed. The buildup of p62 clumps generally indicates that this process is no longer working as it should, as the toxic protein aggregates contributing to ALS are not cleared properly.
“These findings implicate the autophagy pathway in ALS survival and provide support for further study of p62 as a potential prognostic biomarker in ALS,” researchers wrote.
The study, “<a href="https://academic.oup.com/jnen/advance-article/doi/10.1093/jnen/nlad051/7220740?login=false">Survival in sporadic ALS is associated with lower p62 burden in the spinal cord</a>,” was published in the <a href="https://academic.oup.com/jnen">Journal of Neuropathology &amp; Experimental Neurology</a>. The work was funded by Australia’s <a href="https://fightmnd.org.au/">FightMND</a>.
In ALS, the loss of the specialized nerve cells that control voluntary movement, called motor neurons, results in <a href="https://alsnewstoday.com/symptoms-of-als/">symptoms</a> such as muscle weakness and wasting, and an inability to control movement.
Both upper motor neurons, which connect the brain to the spinal cord, and lower motor neurons, extending from the spinal cord to muscles, are affected in people with the disease.
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<h3>Formation of toxic clumps of TDP-43 protein occurs in almost all ALS patients</h3>
A hallmark of ALS, occurring in about 97% of patients, is the formation of toxic clumps of the TDP-43 protein, which contribute to motor neuron loss. The p62 protein, a marker for autophagy, is often found within these TDP-43 aggregates.
In this report, researchers at the University of Sydney investigated p62 aggregates in the motor neurons of 31 <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a> patients to assess p62’s association with TDP-43 accumulation, neuron loss, and survival.
All participants had upper and lower motor neuron degeneration accompanied by TDP-43 protein clumps. A group of 15 patients had short disease duration, defined as less than two years (short survival), while 16 patients had a longer disease duration of 4-7 years (longer survival). There were no differences in age at death, site of onset, sex, or ALS stage between the two groups.
Tissue analysis of donated samples found the density of motor neurons in the spinal cord was significantly lower in patients who lived longer compared with those in the short-disease duration group.
No significant differences in neuron density were observed in the motor cortex, a part of the brain that generates signals to direct body movements, and the hypoglossal nucleus, a prominent cluster of large motor neurons that supply the tongue muscles.
Aggregates of p62 were detected in lower motor neurons, which had three types of structures: thread-like, dense and round, and dot-like. By contrast, p62 aggregates were not seen in upper motor neurons.
A significantly greater density of p62 aggregates was found in the spinal cord of the short-disease duration cases compared with longer duration cases, driven by mainly thread-like aggregates.
“Because the accumulation of p62 is considered an indicator of autophagy inhibition, the present findings of significantly more p62 aggregates in the spinal cord of patients with a shorter disease duration implicates deficits in [autophagy] pathways in ALS survival,” the researchers wrote.
Motor neurons with TDP-43 aggregates were significantly more common in the spinal cord and hypoglossal nucleus of the short compared with the extended survival group. Thread-like aggregates also were more prominent in the spinal cord of those with shorter survival. No significant difference was found in upper motor neurons.
Statistical analysis found a significant correlation between p62 and TDP-43 aggregates, and increasing p62 and TDP-43 aggregates were associated with increasing numbers of spinal cord motor neurons.
ALS patients with longer survival had significantly fewer p62 and TDP-43 aggregates and lower motor neuron density in the spinal cord.
“The present study demonstrates significantly more p62 aggregates in the spinal cord of patients with shorter ALS survival,” the team concluded. “Future longitudinal [over time] studies will be able to determine the viability of in vivo [in living organisms] measures of p62 expression in identifying patients with poorer prognosis at presentation.”

Survival in sporadic ALS linked to autophagy protein p62

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).
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<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.
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<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.

Study uncovers 2 therapies to help target autoimmune inflammation

A sizable portion of people with sporadic <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) carry a genetic mutation known to cause other neurological disorders, a new study shows.
&#8220;This suggests shared risk factors among these diseases, shared mechanisms that cause nerves to die – and perhaps shared therapeutic strategies in the future,&#8221; Kelly Williams, PhD, associate professor at Macquarie University in Sydney and co-author of the study, said in a <a href="https://lighthouse.mq.edu.au/for-media/study-finds-some-mnd-and-dementia-patients-share-genetic-defects">press release</a>. &#8220;While the causes of sporadic [ALS] and FTD [frontotemporal dementia] remain unknown, this is an important step in a long-term effort to identify the risk factors for developing one of these diseases.&#8221;
The study, &#8220;<a href="https://www.science.org/doi/10.1126/sciadv.ade2044">Short tandem repeat expansions in sporadic amyotrophic lateral sclerosis and frontotemporal dementia</a>,&#8221; was published in <a href="https://www.science.org/journal/sciadv">Science Advances</a>.
ALS is characterized by the gradual death and dysfunction of motor neurons, the nerve cells that control movement. While <a href="https://alsnewstoday.com/als-and-genetics/">some mutations</a> have been linked to ALS, the vast majority of people with <a href="https://alsnewstoday.com/sporadic-als/">sporadic ALS</a> have no known mutation associated with the disease.
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<h3>STR expansion can disrupt gene function, cause disease</h3>
Within a person&#8217;s DNA, many genes contain short tandem repeats (STRs) — sequences where a few nucleic acids (the building blocks of DNA) are repeated over and over again. These repetitive regions are important for regulating gene activity.
Sometimes, the repetitive region in STRs will duplicate or expand, so the repeat becomes much longer than normal. This type of mutation, called an STR expansion, can disrupt gene function and cause disease. In fact, the most common ALS-causing mutation is an STR expansion in the gene C9ORF72.
STR expansions in other genes have been shown to cause other neurological disorders. For instance, an STR expansion in the gene HTT is the cause of <a href="https://huntingtonsdiseasenews.com/what-is-huntingtons-disease">Huntington&#8217;s disease</a>, while STR expansions in the genes ATXN1, ATXN2, and ATXN8 cause a group of movement disorders known as spinocerebellar ataxias.
Research on STR expansions has historically relied on time-consuming laboratory tests, but with the recent development of whole-genome sequencing — technologies that can determine the entirety of a person&#8217;s genetic code — it is now much easier to look for these expansions in large groups of patients.
In this study, scientists based in Australia used whole-genome sequencing data to look for STR expansions in people with ALS or the related condition frontotemporal dementia (FTD).
The study included data on 608 people with sporadic ALS, 68 with sporadic FTD, and 4,703 control subjects with no known neurological disease. The researchers specifically looked for 21 STR expansions that have been linked with other neurological disorders.
Among the sporadic ALS patients, 48 carried a mutation that had previously been connected with the disease; 41 had an STR expansion in C9ORF72, three had a mutation in the SOD1 gene, and four had mutations in the TARDBP gene.
Among all 676 ALS and FTD patients, 119 (17.6%) harbored an STR repeat expansion in a gene that&#8217;s traditionally been associated with another disease. There were 12 patients (less than 2%) with expansions in more than one of these genes.
&#8220;We found almost 18 per cent of sporadic [ALS] and FTD patients carried a DNA repeat expansion thought to be involved in other degenerative diseases,&#8221; said Lyndal Henden, PhD, a co-author of the study at Macquarie University. &#8220;Finding this genetic connection between [ALS] and FTD offers a fresh opportunity to uncover common risk factors for neuron death, and it will have implications for understanding both diseases.&#8221;
<h3>Diagnoses consistent with ALS despite other mutations</h3>
In most cases, the detected mutations were intermediate expansions — that is, the STR region contained more repeats than normal, but not so many as to be disease-causing. However, a handful of patients were found to have known disease-causing repeat expansions in genes including the spinocerebellar ataxia genes ATXN8 and ATXN1, as well as FMR1, which causes <a href="https://fragilexnewstoday.com/what-is-fragile-x-syndrome/">fragile X syndrome</a>.
Despite having mutations shown to cause other diseases, clinical data from all these patients &#8220;were consistent with a diagnosis of ALS,&#8221; the researchers wrote.
STR expansions also were seen in more than 1 out of every 10 patients without the disease. However, when including all genes assessed, the overall rate of STR expansions was significantly higher among the patients with ALS or FTD compared with controls (23.2% vs. 16.3%). The researchers stressed further studies will be needed to verify whether and how these mutations influence the development of disease.
&#8220;Rare repeat expansions, such as these identified in this study, may be truly associated with disease risk; however, larger ALS and FTD patient cohorts will be required to determine their significance to disease,&#8221; they wrote.

Tag: sporadic ALS

Survival in sporadic ALS linked to autophagy protein p62

Study uncovers 2 therapies to help target autoimmune inflammation

Some sporadic ALS patients have mutation causing other diseases