Discovery of Molecular Trigger of Motor Neuron Death Could Aid ALS Treatment Research

Researchers have identified the sequence of molecular events leading to motor neuron death in amyotrophic lateral sclerosis (ALS), an important step forward that may lead to new therapies to halt this process.

They found that unlike healthy astrocytes, which are neuron–supporting cells, astrocytes from patients with the disease were unable to keep motor neurons alive, including healthy neurons.

The study, titled “Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS,” was recently published in Cell Reports.

“Understanding how and why neurons die is clearly vital in neurodegenerative diseases, but part of the puzzle is also understanding the emerging role of astrocytes in this context,” Sonia Gandhi, co–author of the study and researcher at Francis Crick Institute and University College London (UCL), said in a press release.

Taking advantage of developmental biology techniques, the research team transformed skin cells collected from three healthy volunteers and two patients with ALS into pluripotent stem cells (iPSCs).

With the right stimuli, iPSCs can become any other cell, enabling researchers to transform them into astrocytes and motor neurons, the cells responsible for controlling muscles and movement.

The cells collected from ALS patients had genetic mutations in a gene called VCP, which is associated with 2% of familial ALS cases. This means that all iPSCs generated from theses samples, and subsequent motor neurons and astrocytes, carried these mutations.

“We manipulated the cells using insights from developmental biology, so that they closely resembled a specific part of the spinal cord from which motor neurons arise,” said Rickie Patani, group leader at the Francis Crick Institute and UCL. “It’s like changing the postcode of a house without actually moving it. We were able to create pure, high-quality samples of motor neurons and astrocytes which accurately represent the cells affected in patients with ALS.”

By tracking the molecular mechanisms occurring in the patient–derived cells and comparing them with those observed in cells from healthy subjects, the researchers could pinpoint what was different and what could be contributing to ALS development.

They found that leakage of a protein called TDP-43 from the nucleus of cells, where it belongs, into the cytoplasm was triggering a series of events that produced stress to the cell. Ultimately, these initial mechanisms led to serious damage to key cellular components, including the cell’s powerhouse, the mitochondria, and finally, motor neuron cell death.

Previous studies already reported that TDP-43 protein leakage and aggregation could be found in about 95% of all ALS cases. This study showed for the first time that this is an early event and the first step toward catastrophic cellular events.

“Knowing when things go wrong inside a cell, and in what sequence, is a useful approach to define the ‘critical’ molecular event in disease,” Gandhi said. “By modeling the human disease in a dish, we found that this well-recognized event in ALS occurred early, and some time before the neurons showed other signs of stress.”

Researchers also evaluated if astrocytes could be involved in this process. They mixed different combinations of healthy and ALS patient–derived motor neurons and astrocytes. They found that healthy astrocytes worked along with ALS motor neurons to keep them alive. In contrast, ALS astrocytes were unable to provide pro–survival signals to ALS motor neurons, failing to protect them effectively from death. ALS astrocytes also struggled to keep healthy motor neurons alive.

“Our work, along with other studies of ageing and neurodegeneration, would suggest that the cross-talk between neurons and their supporting cells is crucial in the development and progression of ALS,” Patani said.

The team is currently working with pharmaceutical companies to translate these findings into new treatments for diseases where motor neuron death is the driving factor, such as motor neuron disorders and other neurodegenerative conditions.

“One therapeutic approach to stop sick motor neurons from dying could be to prevent proteins like TDP-43 from leaving the nucleus, or try to move them back,” Gandhi said.