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Scientists at King&#8217;s College London have identified the site in motor neurons that appears to be the starting point of dysfunction in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) — shedding new light on the workings of the neurodegenerative disease at its earliest stages.
&#8220;This provides a better understanding of the complex mechanism of this disease and a new therapeutic target to improve neuronal function,&#8221; Ivo Lieberam, PhD, a study co-author,  said in a <a href="https://www.kcl.ac.uk/news/specialised-motor-neuron-region-affected-in-amyotrophic-lateral-sclerosis">King&#8217;s College news story</a>.
According to the researchers, motor neurons carrying mutations that cause ALS show abnormal activity in a specialized part of the cell called the axon initial segment, which is where electrical signals are started in these nerve cells.
&#8220;We showed that the axonal initial segment has an important site of dysfunction in motor neurons caused by different genetic mutations,&#8221; Lieberam said.
The study, &#8220;<a href="https://www.cell.com/cell-reports/fulltext/S2211-1247(23)01521-8">Aberrant axon initial segment plasticity and intrinsic excitability of ALS hiPSC motor neurons</a>,&#8221; was published in <a href="https://www.cell.com/cell-reports/home">Cell Reports</a>.
[recommended-reading id=85814]
<h3>Seeking to understand the &#8216;why&#8217; of changes in ALS motor neurons</h3>
ALS is characterized by the death and dysfunction of motor neurons, the nerve cells that control voluntary movement. Normally, motor neurons are activated by signals from the brain, and then send electrical signals down their long, wire-like fibers, known as axons.
When the electrical signal reaches the end of the axon, it prompts the nerve to release signaling molecules to nearby muscle cells, telling the muscle cells to contract.
In ALS, the electrical activity of motor neurons show characteristic abnormalities. In the early stages of the disease, motor neurons are hyperactive, signaling more than usual, which is thought to contribute to <a href="https://alsnewstoday.com/symptoms-of-als/">ALS symptoms</a> such as muscle twitching. Then, in later stages, motor neurons become hypoactive, with less electrical signaling.
In this study, the team of seven researchers aimed to better understand why ALS motor neurons show these changes in electrical activity. For their experiments, the researchers used patient-derived nerve cells carrying mutations in the TDP-43 or C9ORF72 genes, two of the most common ALS-associated genes.
The researchers noted that, although most cases of ALS don&#8217;t have a clear genetic cause, both genetic and non-genetic <a href="https://alsnewstoday.com/forms-of-als/">forms of the disease</a> are typically marked by similar changes in motor neuron activity.
In the early stages of the disease, the scientists found, the ALS motor neurons had abnormally long axon initial segments, or AISs. The AIS is the specific part of the neuron where electrical signals, called action potentials, are started.
&#8220;This study has shown us that the AIS is a key site in the early stages of ALS pathology and requires further investigation,&#8221; said Juan Burrone, PhD, a co-author of the study and professor at King&#8217;s College London.
Normally, the AIS is able to adjust itself, getting longer or shorter to help regulate how often the neuron fires electrical signals. This phenomenon is called plasticity. However, data showed that the AIS had less plasticity in motor neurons carrying ALS-causing mutations — and this lack of plasticity coupled with the abnormally long AIS ultimately caused the neurons to be overactive.
&#8220;Our study shows that increased AIS length and impaired AIS plasticity is an important mechanism driving abnormal regulation of neuronal activity and intrinsic hyperexcitability in early ALS,&#8221; the researchers wrote.
[recommended-reading id=87331]
<h3>Further work needed into other types of ALS-causing mutations</h3>
In cell experiments in which these motor neurons were coupled with muscle cells, the muscles showed twitches similar to what happens in ALS patients, the researchers noted.
Other experiments indicated that the AIS also was dysregulated in later stages of the disease, where it was abnormally short — contributing to reduced activity of the motor neurons. Consistent with these experiments in cell models, analyses of tissue from people who had died from ALS also were indicative of a shortened AIS in the latter stages of the disease.
&#8220;Taken together, our findings point toward an important and dynamic role of the AIS as a site of dysfunction in ALS [motor neurons],&#8221; the scientists concluded.
The team highlighted that this study was limited to cells carrying only two types of ALS-causing mutations, so further work will be needed to determine whether these findings are applicable in all forms of the disease.
[quote=&#8221;center&#8221;]Taken together, our findings point toward an important and dynamic role of the AIS [axonal initial segment] as a site of dysfunction in ALS [motor neurons].[/quote]
Also, further work is needed to understand exactly how AIS abnormalities in motor neurons may alter the activity of other nerve cells and muscle cells that normally interact with motor neurons, the team noted.
&#8220;We now need to expand our investigation across other spinal cord and brain regions and different genetic mutations,&#8221; Burrone said.
&#8220;It will be important to examine whether these structural and molecular changes of the AIS destabilise the neurons somehow, rendering them vulnerable to further pathological insults,&#8221; he said.

Scientists ID site in motor neurons where ALS dysfunction may start

A neuroscientist with a specialty in <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) is joining the faculty at Vanderbilt University Medical Center (VUMC) and will establish an ALS research center at the Nashville school.
Véronique Belzil, PhD, whose work is focused on developing tailored treatments for people with ALS, also will serve as director of the first basic science lab in Tennessee exclusively dedicated to the progressive neurological disease.
She comes to Vanderbilt from the <a href="https://www.mayo.edu/research/faculty/belzil-veronique-ph-d-m-s/bio-20480537">Mayo Clinic in Jacksonville, Florida</a>, where she led work into characterizing the mechanisms that damage and kill motor neurons — the specialized nerve cells that control muscle movement — to <a href="https://alsnewstoday.com/causes-of-als/">cause ALS</a> and the progressive muscle weakness that is a hallmark <a href="https://alsnewstoday.com/symptoms-of-als/">disease symptom</a>.
“The Vanderbilt ALS Research Center will become a natural extension of my own laboratory’s mission: develop patient-centered approaches to quickly bring findings from bench to bedside so ALS becomes curable,” Belzil said.
[recommended-reading id=87929]
<h3>Planned ALS research center sets as its mission finding a disease cure</h3>
The lab will be one of the few U.S. centers focused on translational ALS research, according to Dane Chetkovich, MD, PhD, a professor and chair of the neurology department at VUMC, which Belzil is joining on Jan. 8. Translational research refers to basic science specifically aimed at moving discoveries &#8220;from bench to bedside&#8221; as treatments or the like.
&#8220;Recruiting Dr. Belzil is an important step forward for Tennessee, Vanderbilt, and most importantly the patients and families who need us to do everything we possibly can to find a cure for ALS,” Chetkovich said in a <a href="https://news.vumc.org/2023/11/20/belzil-to-establish-vumc-als-research-center/">university press release</a>.
Belzil has been an assistant professor of neurology at the Mayo Clinic since 2014, where she leads a lab working in ALS,  frontotemporal dementia, a related disease, and other neurodegenerative conditions.
Belzil and her team&#8217;s current research uses human tissue and integrative approaches to identify disease-specific genetic variants and uncover their mechanisms of action in a search for disease biomarkers and potential therapeutic targets. The scientists also use patient-derived cells in work toward gene therapies for ALS and its related disorders.
“Dr. Belzil is a recognized leader in ALS research whose state-of-the-art experimental approaches are well suited to synergize with VUMC’s strengths in genomics and bioinformatics and our goal of making health care personal,” Chetkovich said.
Belzil’s was recruited through a partnership between VUMC with the <a href="https://www.livelikelou.org/">Live Like Lou Foundation</a> — named for Lou Gehrig, the baseball player who died of ALS — that works to support families affected by the disease and research into potential <a href="https://alsnewstoday.com/approved-treatments-for-als/">ALS treatments</a>.
“I am looking forward to establishing a world-renowned collaborative and translational ALS research center by prioritizing open science, teamwork, interdisciplinary expertise, and national and international collaborations,” Belzil said.

ALS research center planned to open at Vanderbilt University

<a href="https://www.athira.com">Athira Pharma</a>’s experimental therapy ATH-1105 shows anti-inflammatory and neuroprotective effects, promoting neuron growth and reducing damage associated with mechanisms of <a href="https://alsnewstoday.com">amyotrophic lateral sclerosis</a> (ALS) and frontotemporal dementia (FTD), a related condition.
The small molecule reduced inflammation and the buildup of a faulty version of TDP-43, a protein that’s thought to drive neuronal damage in both ALS and FTD.
That’s according to new data from preclinical studies in lab-grown cells and a mouse model of the two diseases that were shared in a poster at this year’s Alzheimer’s Association International Conference (AAIC), July 16-20, virtually and in person in Amsterdam, the Netherlands.
The poster was titled “<a href="https://www.athira.com/wp-content/uploads/2023/07/AAIC2023_FTD_L5_6July2023.pdf">ATH-1105, a small-molecule positive modulator of the HGF/MET system, is neuroprotective and attenuates TDP-43 protein pathology in ALS and frontotemporal dementia-relevant preclinical models</a>.”
The findings add to previous evidence that ATH-115 <a href="https://alsnewstoday.com/news/als-mouse-model-sees-prolonged-survival-with-ath-1105/">extended lifespan</a> and <a href="https://alsnewstoday.com/news/ath-1105-aid-nerve-health-motor-skills-als-mouse-model/">improved motor function</a> in ALS mouse models.
“We are encouraged by the growing body of preclinical research supporting ATH-1105, which shows the molecule is protective against several [disease-causing mechanisms] common to ALS and FTD,” Kevin Church, PhD, Athira’s chief scientific officer, said in a <a href="https://www.globenewswire.com/news-release/2023/07/17/2705476/0/en/Athira-Pharma-Presents-Phase-2-Clinical-Data-Correlating-Improvements-in-Biomarkers-of-Neurodegeneration-and-Neuroinflammation-with-Improvements-in-Measures-of-Cognition-and-Functi.html">company press release</a>.
[recommended-reading id=85595]
<h3>Effects of ATH-1105 on ALS, FTD</h3>
Mutations in the TARDBP gene, which codes for TDP-43, have been linked to the risk of <a href="https://alsnewstoday.com/causes-of-als/">developing ALS</a>. The mutations cause the protein to fold into the wrong shape and form toxic clumps.
Nearly everybody (97%) with ALS grow these TDP-43 aggregates in motor neurons, the nerve cells that control voluntary movement and are progressively lost with the disease. The damage results in <a href="https://alsnewstoday.com/symptoms-of-als/#Muscular_symptoms">muscle weakness</a> and an inability to control movement. The aggregates also form in roughly half of people with FTD.
ATH-115 works as a <a href="https://www.athira.com/science/">positive modulator</a> of the HGF/MET system, meaning it activates it. The HGF/MET system is a signaling pathway that helps safeguard neurons from damage by promoting their growth, repair, and survival.
“Positive modulation of the HGF/MET system has been shown to protect against several drivers of neurodegeneration in preclinical models, and this approach may represent a potential therapeutic strategy for ALS and FTD,” wrote the researchers, who tested ATH-115 in lab-grown neurons from the hippocampus of healthy rats. The hippocampus is a brain region linked to memory and learning, and TDP-43 clumps <a href="https://alsnewstoday.com/news/study-links-cognitive-impairment-with-toxic-protein-clumps-in-als/">also build up there</a>.
Neurons treated with ATH-115 grew about twice as many neurites, or projections that form connections with other neurons, and about three times more synapses, which are the points of contact between them.
The effect had about the same magnitude as treatment with HGF, the growth factor in the HGF/MET system.
<h3>ATH-1105 offers protection</h3>
The scientists then used four chemicals in amounts that were toxic to lab-grown rat cortical neurons, or neurons from the brain’s outermost layer. The chemicals were the neurotransmitter glutamate, bacteria-derived lipopolysaccharide (LPS), hydrogen peroxide, and 1-methyl-4-phenylpyridinium, a neurotoxin.
Each of them reduced the number of neurons that remained alive. However, when treated with ATH-1105 beforehand, the neurons were protected against their associated damage and didn&#8217;t die as much. In fact, almost all remained alive.
The researchers then analyzed the effects of ATH-1105 when added to LPS-exposed lab-grown human macrophages, a type of immune cell. LPS exposure increased the cells’ production of IL-6 and TNF-alpha, two pro-inflammatory signaling molecules, while ATH-1105 significantly reduced their levels.
Inflammation induced by LPS can cause cognitive impairment. In mice, this can be studied using a test called a T-maze. Compared with a placebo, ATH-1105 (given by mouth once daily for 14 days) eased cognitive impairment in LPS-exposed mice.
Finally, the researchers used a mouse model of ALS and FTD that produces a faulty version of human TDP-43. Some mice were given ATH-1105 by mouth once daily from 1-3 months of age. Others were given a placebo.
Similar to data from previous preclinical studies, ATH-1105 reduced blood IL-6 and TNF-alpha levels. It also reduced the levels of neurofilament light chain, a marker of neuronal damage.
Moreover, ATH-1105 reduced TPD-43 levels in the mice’s sciatic nerve by about three times, nearly reaching those seen in healthy mice. The sciatic nerve is a long nerve that runs from the lower back down the lower limbs.
“The consistency and breadth of these effects in reducing markers of inflammation, neurodegeneration, and TPD-43 protein pathology continue to support the broad therapeutic potential and continued advancement of ATH-1105,” Church said.

ATH-1105 protects against common ALS, FTD disease mechanisms

<a href="https://www.neurosense-tx.com/">NeuroSense Therapeutics</a> has joined researchers at Massachusetts General Hospital to study the impact of its investigational therapy PrimeC on key <a href="https://alsnewstoday.com/what-is-als/">amyotrophic lateral sclerosis</a> (ALS) processes.
The collaboration will the headed by Ghazaleh Sadri-Vakili, director of the Neuroepigenetics laboratory at the MassGeneral Institute for Neurodegenerative Disease. Using a new laboratory model generated from post-mortem brain tissue samples, the researchers seek to know more about PrimeC&#8217;s mechanisms of action in ALS.
&#8220;We are excited to join NeuroSense in its mission to advance PrimeC for people living with ALS,&#8221; Sadri-Vakili said in a <a href="https://www.prnewswire.com/news-releases/neurosense-therapeutics--massachusetts-general-hospitals-neuroepigenetics-lab-to-collaborate-on-elucidating-neurotherapeutic-effects-of-primec-in-als-301781895.html">company press release</a>. &#8220;Our in vitro model may serve as an effective tool to increase our understanding of PrimeC&#8217;s neurotherapeutic mechanism of action.&#8221;
PrimeC is an extended-release oral formulation that combines a fixed dose of the antibiotic ciprofloxacin and the anti-inflammatory celecoxib. Both are individually approved by the U.S. Food and Drug Administration and have established safety profiles.
The combination therapy is thought to target multiple disease processes in ALS, including iron accumulation, faulty RNA processing, inflammation, and motor nerve cell degeneration.
In a previous <a href="https://clinicaltrials.gov/ct2/show/NCT04165850">Phase 2a trial (NCT04165850)</a>, the original formulation of PrimeC markedly <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">reduced levels of ALS biomarkers</a> and showed trends toward lower disease progression rates and lung function declines compared with historical controls.
In particular, it <a href="https://alsnewstoday.com/news/primec-safe-lowers-als-disease-biomarkers-phase-2-clinical-study/">reduced the amount of TDP-43</a>, a protein that&#8217;s abnormal in most ALS cases, in neuron-derived exosomes (NDEs) — packets of cellular cargo released by nerve cells into the extracellular space.
As part of the new collaboration, Sadri-Vakili and her team will explore how PrimeC affects TDP-43 accumulation in patients. The scientists will also try to unravel how it works to reduce other disease mechanisms, including defects in autophagy (the process by which cells recycle faulty or unwanted molecules) and abnormalities in mitochondria, the cells energy-producing factories.
Its impact on oxidative stress, another ALS-related process caused by an imbalance between reactive oxygen-containing molecule production and the body&#8217;s ability to clear them, will also be investigated.
[recommended-reading id=78033]
<h3> Study to explore PrimeC&#8217;s effects on oxidative stress, mitochondrial defects</h3>
To address that, the researchers will use vesicles derived from nerve tissue from ALS patients and control subjects after death. The team has shown these vesicles can induce oxidative stress and mitochondrial defects in cell cultures.
They aim now to see how much these processes are impaired when cells are treated with the vesicles in the presence of PrimeC. They&#8217;ll also compare the effects of the individual components of PrimeC, celecoxib and ciprofloxacin, with those seen with the combination therapy.
“We are pleased to formally establish this important collaboration with Dr. Sadri-Vakili&#8217;s team, where we hope to elucidate PrimeC&#8217;s efficacy via key measurements that correlate with our Phase 2b ALS study endpoints,” said Shiran Zimri, PhD, vice president of research and development at NeuroSense.
PrimeC was granted orphan drug status in the U.S. in 2020 and in Europe the following year. The designation is given to potential treatments for rare diseases to accelerate their development and possible regulatory review.
The extended-release formulation of PrimeC is being investigated in the Phase 2b <a href="https://clinicaltrials.gov/ct2/show/NCT05357950">PARADIGM trial (NCT05357950)</a>. The trial is <a href="https://alsnewstoday.com/news/paradigm-trial-testing-als-therapy-primec-drops-u-s-sites/">enrolling about 69 patients</a>, ages 18-75, at multiple sites in Israel, Canada, Germany, and Italy.
In addition to standard ALS therapies, participants will be randomly assigned to receive PrimeC — two oral tablets twice daily for a total of 1,496 mg a day — or a placebo for six months.
The trial&#8217;s main goals are to determine the therapy&#8217;s safety and impact on disease biomarkers. Other, secondary measures include changes in the rate of disease progression, lung function and quality of life declines, and survival. Top-line data are expected later this year.

Tag: disease mechanisms

Scientists ID site in motor neurons where ALS dysfunction may start

ALS research center planned to open at Vanderbilt University

ATH-1105 protects against common ALS, FTD disease mechanisms

Collaboration to study PrimeC’s impacts on ALS disease mechanisms