Researchers have developed a stem cell-based model to provide information about neuron resilience in ALS

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Researchers at Karolinska Institutet in Sweden have developed a stem cell-based model to study the resilience and vulnerability of neurons in the neurodegenerative disease ALS.

The results are published in the journal Stem Cell Reports, and could aid in the identification of new genetic targets for treatments protecting sensitive neurons.

Amyotrophic lateral sclerosis, ALS, is a fatal disease with no effective treatment or cure.

Amyotrophic lateral sclerosis (ALS) is an incurable condition, characterised by progressive degeneration of upper and lower motor neurons, resulting in paralysis and death from respiratory failure in a median of 2–3 years 1.

Despite the poor prognosis, there is considerable variation in the survival rate, and up to 10% of people with ALS live for more than 8 years from first symptoms 2.

Understanding what causes ALS or influences survival is crucial for the development of effective treatments.

The causes of ALS are largely unknown.

Significant advances have been made in understanding the genetic and environmental components of the disease.

ALS presents in many different ways ( Table 1), and it has been recognised for many years that the different clinical presentations correspond with differences in survival 1112.

Bulbar palsy, in which dysarthria followed by swallowing difficulty is the main presentation, is associated with the worst prognosis, and flail arm or flail leg syndrome, in which there is symmetrical, predominantly flaccid weakness of the limbs, is associated with the best prognosis 13.

Perhaps surprisingly, statistical methods such as latent class cluster analysis can analyse the same data and identify different clinical subtypes that predict prognosis with far more discrimination than can neurologist classifications 13.

Most cases of ALS are focal in onset and relentlessly progressive, often to contiguous regions, although there are some exceptions 14.

The spread could be the result of a “prion-like” spread of toxic proteins through phagocytosis (consumption of cells by other cells) or possibly through a time-to-failure model 15– 17.

Lower motor neuron failure is the main cause of weakness in ALS and can be measured non-invasively to provide data to assess cellular patterns of spread 18.

Understanding the mechanisms of spread will aid the development of novel therapeutics and may aid models of prognosis.

Table 1.

Clinical presentations of amyotrophic lateral sclerosis.

Classifying 
feature
Name of phenotypeDescription
Motor neuron 
involvement
Amyotrophic lateral 
sclerosis (ALS)
Mixture of upper and lower motor neuron signs on clinical examination. 
Degree of certainty of diagnosis based on El Escorial criteria. May 
involve up to all regions.
Primary lateral sclerosis 
or upper motor neuron 
predominant ALS
Clinical signs limited to upper motor neuron features. Generally slowly 
progressive but involving up to all regions. This phenotype is usually 
confirmed if there have been no lower motor neuron signs after 4 years.
Progressive muscular
atrophy or lower motor 
neuron predominant ALS
Clinical signs limited to lower motor neuron features. Slightly slower 
progression but can involve all regions. This phenotype is usually 
confirmed if there have been no upper motor neuron signs after 4 years.
Site of onsetBulbar onsetSite of onset may be included in the description of ALS, as different 
disease onset patterns have different rates of progression. The two 
categories are bulbar and spinal.
Spinal onset
Disease 
focality
Progressive bulbar palsyCondition involving the bulbar region and predominantly lower motor 
neurons. May progress to other regions.
Pseudobulbar palsyCondition involving the bulbar region and predominantly upper motor 
neurons. May progress to other regions.
Flail armPredominantly lower motor neuron proximal symmetrical involvement in 
the upper limbs. Some upper motor neuron signs may be seen in the 
lower limbs.
Flail legLower motor neuron distal symmetrical involvement restricted to the lower 
limbs. May affect one side only.
Cognitive 
involvement
ALS with cognitive 
impairment
ALS with some cognitive involvement below the threshold criteria for 
frontotemporal dementia.
ALS with frontotemporal 
dementia (ALS-FTD)
ALS with frank frontotemporal dementia.

The disease is characterised by a loss of neurons controlling voluntary muscles, known as motor neurons.

This causes muscle atrophy, weakness and eventually paralysis.

However, some groups of motor neurons are highly resilient and can survive all stages of the disease.

These include the neurons that control our eye movements, the oculomotor neurons.

Exactly why these motor neurons can withstand the disease is currently unknown.

The oculomotor neurons are few, found in the brain stem and are difficult to study in humans and animals.

In order to further investigate the differences in sensitivity between different motor neurons, it would thus be advantageous if cultivated stem cells could be used.

One such stem cell based model of neuron resilience in ALS has now been developed by researchers at Karolinska Institutet.

“This cell culture system can help identify new genes contributing to the resilience in oculomotor neurons that could be used in gene therapy to strengthen sensitive motor neurons,” explains Eva Hedlund, docent at the Department of Neuroscience at Karolinska Institutet, who led the study.

The work builds upon the KI researchers having succeeded in generating oculomotor neurons from cultivated embryonic stem cells.

This was achieved by overexpressing the transcription factor PHOX2A, which is necessary for the formation of oculomotor neurons during an embryo’s development.

By performing various analyses of the cells and by similarities with their equivalents in mice and humans, the researchers conclude that the cells generated are indeed oculomotor neurons.

The researchers show that these resilient neurons generated from stem cells activate a survival-enhancing signal known as Akt, and that this signal is also activated in oculomotor neurons in humans.

The oculomotor neurons that were generated in the lab also appeared more resilient to ALS-like degeneration when compared to spinal cord motor neurons—something which is also seen in humans.

“All in all, this shows that we have created a robust model for studying mechanisms for neuron resilience and vulnerability in ALS,” says lead author Ilary Allodi, who worked with the study as a postdoc in Eva Hedlund’s research group.

More information: Ilary Allodi et al, Modeling Motor Neuron Resilience in ALS Using Stem Cells, Stem Cell Reports (2019). DOI: 10.1016/j.stemcr.2019.04.009
Journal information: Stem Cell Reports
Provided by Karolinska Institutet

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