Researchers identify another piece of the ALS puzzle
A new study provides additional confirmation that reduced levels of a protein called stathmin-2 (STMN2), caused by TDP-43 dysfunction, likely contributes to the progression of ALS.
Abnormalities in a protein called TDP-43 are present in approximately 97 per cent of all ALS cases. Normally, TDP-43 is found in the nucleus of a cell (a central compartment where our DNA is located); however, in people living with ALS it is often found in the cytoplasm (the area outside of the nucleus) where it tends to form clumps, or aggregate, and is no longer able to function properly.
Two landmark studies in 2019 (1,2) revealed that when the amount of functional TDP-43 is decreased within cells, the level of another protein, STMN2, is substantially decreased. Patient tissues analyzed by researchers also showed that STMN2 levels are lower than expected specifically in motor neurons.
The results from the previous studies demonstrated a clear relationship between TDP-43 and STMN2 but left researchers uncertain whether loss of STMN2 directly contributes to disease progression. In this new study, researchers at Washington University sought to answer this question. Using genetic engineering techniques, researchers developed mice that made lower levels of the STMN2 or were unable to produce the protein entirely.
After observing the mice, they found that reduced STMN2 led to functional impairments like those seen in ALS. Further analyses revealed that the functional impairments likely resulted from changes at the neuromuscular junction, the place where motor neurons connect to muscle fibers, which is often considered an early feature of ALS pathology.
These findings support the idea that a reduction in STMN2 resulting from TDP-43 dysfunction contributes to ALS and suggest that methods to preserve the levels of STMN2 within motor neurons may have a therapeutic benefit in people living with ALS. An experimental treatment currently under development by QurAlis, called QRL-201, aims to do just that. QRL-201 is a genetic therapy targeted towards STMN2 that is expected to enter clinical trials later this year. The potential for STMN2 to act as a biomarker for ALS is also being explored by Dr. Vincent Picher-Martel, the recipient of a 2021 ALS Canada Clinical Research Fellowship. You can read more about his study here.
Early studies exploring the potential of a blood pressure medication as a treatment for ALS
Pre-clinical studies in animal models suggest that terazosin, a medication approved to treat high blood pressure, may show promise as a treatment for ALS.
Previous studies have indicated that increased metabolism (called hypermetabolism) is a common feature of ALS and can be associated with weight loss, which is often related to a poorer prognosis. An important protein linked to metabolic pathways within the body is phosphoglycerate kinase 1 (PGK1). The activity of this protein has been shown to be affected in various models of ALS.
Terazosin is an oral medication approved to treat high blood pressure and enlarged prostates that is known to act on PGK1. Terazosin was previously shown to have a neuroprotective effect in models of stroke, spinal muscular atrophy (SMA) and Parkinson’s disease, which led researchers to question whether this neuroprotective effect could translate to ALS as well.
In this study, researchers looked at the effects of terazosin in cell, zebrafish, and mouse models of ALS. They found that treatment with terazosin improved the health of motor neurons in zebrafish, delayed disease progression and increased survival in mice, and protected against cell death induced by oxidative stress in lab culture models. Researchers believe the neuroprotective effects of terazosin are related to its impact on a specific metabolic pathway, called glycolysis, as well as another cellular process frequently linked to ALS, called stress granule formation.
While these results are promising, human clinical trials will be needed to assess whether terazosin can have a positive therapeutic effect in people living with ALS. The research team plans to conduct a small feasibility study in the UK, where 50 invited participants will be followed to examine the effect terazosin has on a few key indicators of disease progression. If successful, the team hopes to move terazosin forward to a full clinical trial.
Harnessing the power of artificial intelligence (AI) to uncover new therapeutic targets for ALS
Using an AI-powered discovery platform, called PandaOmics, researchers analyzed massive datasets of patient information to uncover new genes related to ALS, which could serve as potential targets for future treatments.
It is estimated that the four major ALS-associated genes (SOD1, TARDBP, C9ORF72 and FUS) only account for approximately 50 per cent of ALS cases with a known family history (termed familial ALS) and 5 per cent of sporadic cases. This means that a large portion of the genetic basis of ALS is yet to be discovered.
As part of a collaboration with Insilco Medicine and Answer ALS, a team of researchers set out to identify additional genes that could contribute to disease-driving mechanisms in ALS. To do so, the team analyzed post-mortem tissue samples from 237 patients and 91 healthy controls, as well as patient-derived motor neurons from 135 patients and 31 healthy controls.
With such a large data set, researchers turned to the AI-powered discovery platform PandaOmics that produced a list of 28 genes predicted to be linked to ALS, of which 17 were said to be “high-confidence targets” and 11 were considered “novel therapeutic targets.”
To validate these findings, researchers examined the effects of the predicted genes in fruit flies carrying mutations in the C9ORF72 gene, the most common genetic cause of ALS. Without intervention, these flies will experience neurodegeneration which leads to alterations in eye shape and function. Of the 28 target genes identified, 26 were screened in the fruit flies and 18 reduced eye neurodegeneration when suppressed, suggesting that these genes (8 of which have not been reported on before) could serve as potential targets for future ALS treatments. Further studies are required to determine the exact role these newly identified genes may play in ALS.
This work highlights the power of AI technology to help researchers better understand the biology of ALS. Identifying promising treatment targets is the first step in therapeutic development, and AI technology could help researchers do this much faster than conventional methods.
New insight into cellular processes that may be affected at early stages of disease
Alterations to NOVA1, a protein involved in an important cellular process called alternative splicing, may contribute to early dysfunction in ALS.
Since it was first identified in 2006, researchers have suspected that TDP-43 is an important piece of the ALS biology puzzle. In almost all ALS cases, a characteristic build-up of abnormal TDP-43 clumps can be seen within motor neurons late in the process of their degeneration. However, what happens before TDP-43 dysfunction occurs is still unknown.
In this study, researchers set out to better understand changes happening early on within a cell that may contribute to ALS, particularly focusing on a process linked to protein formation called alternative splicing.
DNA carries the master code of genetic instructions for all processes that take place within the body. When DNA is “read” another genetic molecule is created, called RNA, from which proteins are then made. Alterative splicing allows for certain sections of the RNA molecule to be added or removed which in turn can enhance, reduce, or change the function of the resulting protein. Sometimes this complex process can go wrong, leading to the creation of unusual or toxic proteins that contribute to disease.
Using motor neurons derived from ALS patients, researchers analyzed changes in the network of RNA-binding proteins that regulate alternative splicing, before TDP-43 dysfunction occurs. The function of one protein in particular, called NOVA1, appeared to be disrupted early on, significantly influencing alternative splicing patterns.
The results from this study suggest that alterations to RNA-biding proteins, such as NOVA1, may disrupt alternative splicing within cells and contribute to ALS. Further, these changes likely occur early on before TDP-43 dysfunction. While further studies are required to determine exactly how these changes lead to motor neuron death, this work opens new avenues to explore when developing therapeutic strategies aimed at treating the disease in its earlier stages.
Advances in identifying a novel biomarker for ALS
Researchers have identified a substance found in the blood that appears to be elevated in people affected by ALS.
There is an unmet need for inexpensive, non-invasive, and accurate biomarkers in neurogenerative diseases like ALS. Biomarkers are biological measures that can be used to understand the real-time processes happening in the body. For example, the level of cholesterol in the blood is a biomarker for the risk of heart disease and is used as an indicator of a person’s response to cholesterol-lowering drugs. Validated biomarkers are urgently needed to help clinicians diagnose ALS, track progression of the disease and measure response to therapies.
Previous studies have shown that elevated levels of a substance called phosphorylated tau at threonine 181 (p-tau181) in the blood and cerebrospinal fluid (CSF) is a marker of Alzheimer’s disease (AD). When investigating this finding, researchers inadvertently discovered higher than expected levels of p-tau181 in 11 patients with ALS.
In this study, the researchers expand on their preliminary observation to determine whether p-tau181 may serve as a marker of ALS as well. The team analyzed blood and CSF samples from 130 patients with ALS, 89 patients with AD and 33 healthy controls. They found that unlike in AD where p-tau181 was elevated in both blood and CSF samples, in ALS patients p-tau181 levels were only elevated in the blood. In fact, p-tau181 levels in the CSF were consistently low in ALS patients.
Further analyses of patient tissue samples revealed that the elevated p-tau181 levels in the blood of ALS patients was likely a response to lower motor neuron dysfunction. Upper motor neurons originate in the brain and carry signals for voluntary movement from the brain to the spinal cord. Lower motor neurons, on the other hand, originate in the spinal cord and carry these signals from the spinal cord out to the muscles. These finding suggest that blood levels of p-tau181 could serve a novel biomarker for lower motor neuron dysfunction in ALS.
The researchers note some limitations to this work and add that additional studies with larger samples sizes are needed to validate these findings. However, the data suggests that p-tau181 may represent a minimally invasive biomarker for ALS that could someday be used to help support earlier diagnosis, inform disease management, and evaluate the effectiveness of emerging therapies being tested in clinical trials.
