ALS researchers from around the world continue to build upon existing work and make new discoveries in the hopes of realizing a future without ALS. In the October 2021 Research Update, you’ll learn about the progress researchers have made in identifying new ALS risk factors and treatment targets, increasing our understanding around how the body may compensate for motor neuron loss early in disease progression, detangling the complex biology that underlies gene regulation in ALS and studying a new imaging biomarker that could help to give researchers the tools they need to better evaluate the effectiveness of promising new treatments.

New target identified as potential treatment for both sporadic and familial ALS

Researchers believe they have identified an early event that may spark the cascade of cellular dysfunction that ultimately leads to motor neuron death in both sporadic and familial ALS.

Scientists have learned a lot about the end stages of ALS, but far less is known about the early cellular events that trigger the disease. For example, changes in the nuclear pore complex (NPC; large protein complexes responsible for moving substances between the nucleus and cytoplasm of a cell) have been shown to play a role in ALS, leading to many downstream consequences but when those changes start to occur and what causes them remains unknown.

A specific protein called CHMP7 is known to play a role in maintaining the proper functioning of NPCs. In this study, researchers studied induced pluripotent stem cell-derived motor neurons from people living with ALS and found that CHMP7 was present a higher-levels in the nucleus of cells from ALS patients.

Additional studies revealed that the observed build-up of this protein within the nucleus seemed to be driving NPC damage as a potential early trigger of motor neuron damage. Furthermore, CHMP7 is not even meant to be in the nucleus and its mislocalization from the cytoplasm appears to cause mislocalization of another important protein, called TDP-43, which is a critical marker of almost all cases of ALS. Using antisense technology, the researchers then eliminated CHMP7 from cells and found that this reduced NCP dysfunction, TDP-43 mislocalization and ultimately cell death.

These observations suggest that therapies targeting CHMP7 may represent a promising avenue to explore when developing new treatments for both sporadic and familial ALS. By targeting early events in the disease process, researchers are hopeful that they may be able to prevent the downstream effects that lead to motor neuron death.

Large scale genetic study identifies new risk factor for sporadic ALS

A new large-scale genetic study has recently revealed that rare mutations in a gene, called TP73, may increase a person’s risk of developing sporadic ALS.

Both genetic and environmental factors are thought to play a role in the development of sporadic ALS (i.e., cases with no family history). To identify new potential genetic risk factors for the disease, a team of researchers collected blood samples from 87 people living with sporadic ALS and 324 healthy controls. Using a technique called exome sequencing, they found that five individuals with sporadic ALS had rare mutations in the TP73 gene.

The researchers then expanded the study to include nearly 2,900 participants and in the end identified a total of 24 different, rare mutations in TP73. This gene produces a protein, called p57, that helps to regulate the life cycle of a cell. Within the nervous system specifically, it acts to promote nerve cell survival by inhibiting specific cell death pathways. Additional studies using muscle cells grown in the laboratory revealed the production of the normal p57 protein is essential to nerve cell health and that mutations in this gene have a damaging effect on the protein’s normal function.

Overall, the results suggest that mutations in TP73 increase the risk of ALS and do so by failing to suppress specific cell death pathways. This discovery provides a new target for researchers working to develop therapies to slow or even stop the progression of ALS.

Brain imaging study identifies biomarker that reports on disease progression

A team of Canadian researchers, led by Dr. Sanjay Kalra at the University of Alberta, have found that N-acetylaspartate (NAA) levels, a marker of neuronal health, can serve as an indicator of disease progression in ALS.

The Canadian ALS Neuroimaging Consortium (CALSNIC) is a multidisciplinary team of experts from across Canada that includes neurologists, magnetic resonance imaging (MRI) scientists, computing scientists, neuropathologists, and a biostatistician. Funded in part by the ALS Society of Canada through a 2015 ALS Canada-Brain Canada Arthur J. Hudson Translational Team Grant, this national initiative aims to develop advanced MRI methods to find biomarkers in people with ALS and related conditions.

In this study, 76 people living with ALS and 59 healthy controls were enrolled at five sites across Canada. Using harmonized protocols developed through the CALSNIC platform, participants underwent clinical evaluations and magnetic resonance spectroscopy (MRS) three times over a period of eight months. NAA levels were quantified in different regions of the brain and compared with clinical data, which ultimately allowed researchers to separate participants into different subgroups based on disease progression rate, upper motor neuron (UMN) signs and cognitive abilities.

Researchers found that people living with ALS had decreased NAA levels in their motor cortex, the region of the brain associated with voluntary movement, at their first visit compared to healthy controls. Additionally, those with a more rapid disease progression and greater UMN involvement showed a greater reduction in NAA, which further decreased over time, compared to those with a slower progression or fewer UMN signs. Decreased levels of NAA in the prefrontal cortex, which is thought to play a role in things like planning, decision making, personality and social behaviour, were only observed in participants who displayed cognitive impairments.

The data shows that progressive degeneration of the motor cortex, as observed by NAA levels, is associated with a more rapid disease progression and greater UMN signs in people living with ALS. Development of a non-invasive biomarker like this may help clinicians to better separate patients into subgroups when testing new drug treatments and ultimately help to improve the design and success of future ALS clinical trials.

How does the body compensate for motor neuron loss in ALS?

Usually before someone shows loss of function associated with ALS, there has already been a significant loss of motor neurons suggesting that in the early stages of the disease, the body may be able to compensate for the lost connections between motor neurons and muscles. New research indicates that cholinergic-boutons (C-boutons), specialized synapses shown to influence motor neuron activity, may play a role in this compensation.

C-boutons were first identified over 50 years ago, but until recently their function was not known. In 2009, research in mice conducted by Dr. Turgay Akay at Dalhousie University showed that C-boutons were responsible for changing the excitability of motor neurons and that the level of excitability depended on what the mice were doing. For example, with swimming motor neurons are significantly more excited and produce higher muscle activation than with walking. The data showed that similar to how a volume dial on a radio controls sound output, C-boutons can “turn up the volume” to control how motor neurons respond.

In a recent study, funded in part by the ALS Society of Canada through a 2017 Project Grant, Dr. Akay and his team found that while C-boutons increased the excitability of surviving motor neurons to compensate for motor neuron loss during ALS disease progression, over time the increased stress placed on these motor neurons actually worsens disease progression.

Using a mouse model of ALS, the researchers found that over time mice whose C-boutons were genetically silenced (i.e., non-functional) did better than their untreated counterparts. Additionally, when the C-boutons are silenced, and mice are encouraged to frequently perform exercises designed to otherwise activate the C-boutons, such as swimming, loss of function is slowed when compared to the untreated mice.

Taken together, the results suggest that C-bouton-targeted therapies may be beneficial for people living with ALS and over time could result in improved mobility and quality of life.

New insights into the role that gene regulation may play in ALS

Researchers have identified a substance, called miR-218, that is found at lower-than-normal levels in people living with ALS. This reduction is thought to contribute to the onset and progression of disease.

MicroRNAs (miRNAs) are small molecules of RNA that target messenger RNA (mRNA), the intermediate molecule derived from DNA that is used to create proteins in cells. MiRNAs regulate gene activity by binding to specific mRNAs and preventing generation of their respective proteins.

In this study, researchers found that miR-218 was decreased in people living with ALS but not completely lost, so they decided to study if a particular level of miR-218 is required for motor neurons to function properly. Using a mouse model of ALS, the researchers found that miR218 levels above 36 per cent of what would be seen in healthy individuals resulted in normal signaling between neurons and muscles. However, anything below the 36 per cent threshold resulted in signaling deficits which below 7 per cent became lethal.

Further analyses revealed that miR-218 regulates the activity of approximately 300 different genes within cells, many of which have been shown to play a role in neuromuscular communication. The finding that subtle changes in miR-218 levels can alter gene activity in cells, rather than a simple on-off switch, reveals a more dynamic and complex gene regulation network than previously understood.

This study provides the foundation for understanding how fine-tuning the levels of certain substances, such as miR-218, can influence disease progression and may eventually lead to the development of new treatment targets.

Bringing you the latest news on advancements in ALS research, the ALS Canada research team regularly summarizes the most significant discoveries throughout the year.

Note: We have included links to the publications because we know you may be interested in the original source papers. While abstracts are always available, many journals are subscription based, and in some cases, full papers may only be accessed at a cost.

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