A new study has found that motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), may slow the movement of essential molecules and reduce growth inside nerve cells, even before the cells begin to die. These findings could help identify early disease changes and reveal new therapeutic targets.

ALS affects the motor neurons that transmit signals from the brain to the muscles, leading to progressive weakness and difficulty with movement. While some cases are inherited (familial ALS or fALS), around 90% occur without a family history and are considered sporadic ALS (sALS). The causes behind sALS are still poorly understood, making this study an essential step toward understanding how the disease develops.

Slower transport and growth in human motor neurons

The study, published in Neurobiology of Disease, used human cells rather than animal models to explore how ALS affects motor neuron function. Researchers collected blood samples from men living with sporadic ALS and from healthy men of the same age.

These blood cells were reprogrammed into stem cells, which were then differentiated into motor neurons, the type of nerve cell affected in ALS. The researchers then compared how these neurons functioned between people with and without the disease.

They found that mitochondrial transport, the energy-producing parts of cells, was slower in motor neurons derived from people with ALS. This transport slowed even further as the cells aged. ALS-derived neurons also grew less and showed weaker connections to muscle cells than those from healthy controls.

These results suggest that sporadic ALS cells have problems with transport, growth, and connection,  similar to what has been seen in familial ALS.

Changes to cell instructions and links to disease severity

The researchers also examined RNA, the “instructions” cells use to build and repair themselves, and found changes in genes linked to neuronal structure and growth. These altered instructions led to unusually high production of some materials and low production of others, disrupting normal cell function.

Importantly, the neurones showing the most transport and growth defects came from people who experienced faster disease progression. Those with milder effects had slower progression, suggesting these cellular changes might reflect disease severity at an early stage.

Early cellular changes occur before significant damage occurs

Despite these transport and growth issues, the researchers did not see two key signs of later disease: the abnormal movement of the protein TDP-43 and increased cell death. This means the defects occurred while cells were still alive and functioning, potentially marking one of the earliest stages of the disease process.

These early changes could therefore provide valuable clues about how ALS begins and progresses, and may help identify new ways to detect or treat the disease before irreversible damage occurs.

What does this mean for MND research?

This study demonstrates that sporadic ALS, the most common form of the disease, shares key cellular defects previously seen in familial ALS. It also establishes a reliable human model for studying sporadic ALS, which could help accelerate future research.

While the study included only ten samples (five from people with ALS and five controls), its detailed approach offers a foundation for larger studies, including those involving women, who make up around 40% of people living with ALS.

By identifying early problems in how motor neurons grow and transport materials, this research provides important insights that could inform new treatment strategies and improve understanding of disease onset.

This research snapshot was created using the University of Sheffield’s Readable Research series, which turns technical science into clear, meaningful updates for the MND community. A lay summary of the above research paper is available here.

Original study:
Ye L, Van Den Bosch L et al. Sporadic ALS hiPSC-derived motor neurons exhibit axonal defects associated with altered axon guidance pathways. Neurobiology of Disease, March 2025. DOI: 10.1016/j.nbd.2025.106815