Lay summary by Charlotte Gale, reviewed by Raquel Martins and an MND lay panel.
Background
Amyotrophic lateral sclerosis (ALS) is the most common type of motor neuron disease, with a life expectancy of 2-5 years from diagnosis. ALS is characterised by the loss of cells in the nervous system, which are responsible for sending instructions to muscles. In consequence, the disease leads to reduced muscle function and movement impairment. In the minority of ALS cases there is a family history of the disease (fALS), but up to 90% of cases have no family history and are considered sporadic (sALS).
Key components need to be moved inside cells to allow them to function healthily. For example, building blocks are taken to repair damage and waste products are sent to recycling centres within cells. This process can be disrupted in ALS, and has been widely studied in fALS, but has not been as well studied in sALS. Important structures that are moved around a cell to guarantee the proper function of the cells include mitochondria. Mitochondria are the powerhouse of the cell, which means they release energy to keep the cells alive and working properly. Issues with the movement of mitochondria have specifically been associated with fALS. Another problem found in fALS is that motor neuron cells do not grow as fast and can lose their structure.
Why is the study important?
Although sALS is more common, it can be harder to investigate than fALS due to its lack of family history. The causes behind sALS are less well understood, so this study is very important in building up our understanding of sALS.
Another reason why this study is important is that it uses human cells, rather than animal models such as mice, zebrafish, or fruit flies. Human skin or blood cells are first persuaded to return to being stem cells, effectively embryonic cells, which can develop into any kind of cell. These stem cells can then be converted into human motor neurons. This is currently the most accurate model we have for human motor neurons from people with ALS and people who do not have ALS, the controls.
What did the authors do and how did they do it?
Blood samples were collected from men with sALS, as well as from healthy controls – men of the same age without ALS. One of the strengths of the study is that they only took 5 control and 5 sALS samples in total, which is what enabled them to do so many different experiments. Cells from the blood were converted into stem cells which were then converted into human motor neurons, a type of cell significantly affected in ALS. The authors then compared cell functions, such as cell growth and the movement of mitochondria, and disease characteristics between these human motor neuron cells from men with sALS and the healthy controls.
What are the results?
The authors investigated how well mitochondria were transported through the neurons derived from patients and healthy donors. This process was slower in cells derived from sALS patients and became even slower as the cells aged. After ageing, fewer mitochondria were being moved in cells derived from sALS patients compared to those derived from healthy donors. The sALS cells were also found to grow less than control cells and had issues in connecting to muscles. These results suggest that sALS cells have issues with transport, growth, and function, similar to those previously seen in neurons from patients with fALS.
The authors also looked at the instructions made by the cell nucleus, called RNA, which control the processes outside the nucleus in the cell. There was disruption to the RNA instructions related to the structure and growth of the motor neurons, and these altered instructions were causing abnormally high production of some materials in the cells and abnormally low production of others. These changes in RNA instructions in these sALS neurons are similar to other changes previously found in neurons from patients with fALS.
An additional interesting finding was that the cells that showed the biggest decreases in transport and growth were taken from people who had a faster disease progression, whereas those with the mildest effects had longer survival.
The authors also investigated disease characteristics in the neurons. The first is a protein called TDP-43, which moves out of the nucleus into the wrong part of cells in 97% of ALS cases. Contrary to what was expected, this protein was expressed in the correct place in both the sALS and control cells, and it was working well in both cases. Secondly, the authors found that the sALS cells were not dying more or displaying increased DNA damage when compared to controls. Therefore, these findings in sALS motor neurons of disrupted mitochondrial transport and abnormal RNA instructions occurred while TDP-43 was working correctly. This is before the disease process had progressed to cause movement of the TDP-43 from the nucleus and before cell death had begun, indicating this happens at an early stage of disease.
As mentioned above, one of the study’s strengths was the ability to perform a wide range of work by studying samples from only 5 people living with sALS and 5 control samples, all male so that gender effects did not confuse the results. However, these strengths are also the biggest weaknesses of the study. The research team have established robust and very successful protocols to study sALS using human motor neurons. These methods should now be used to investigate much larger numbers of samples from people living with sALS as well as controls not living with ALS. The studies should also include samples from women living with sALS and female controls, since women make up about 30% of people aged 50 or less living with ALS and about 44% of people aged 51 or more living with ALS.
What do the findings mean going forward for people with the disease?
This study may indicate that cellular transport and growth defects can be an early aspect of sALS disease and could potentially be markers for disease severity and progression speed at an early stage. Disruptions to transport and structure have been found in fALS cells before but were previously not so well known in sALS.
This study establishes a robust human sALS model and demonstrates that it shows the same defects previously studied in fALS. This could help identify new therapeutic targets for sALS, which is more common (affecting 90% of the patients) but has previously been less researched than fALS.
This study can be found at
www.sciencedirect.com/science/article/pii/S0969996125000312?via%3Dihub
Paper title
Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways
Lead author
Lisha Ye, Ludo Van Den Bosch
Publication details including date of publication
Published in Neurobiology of Disease in March 2025. DOI 10.1016/j.nbd.2025.106815