A new study by Stockholm University and King’s College London uncovers early mitochondrial dysfunction in ALS, offering new hope for early intervention and treatment.
Researchers from Stockholm University and the UK Dementia Research Institute at King’s College London have made a groundbreaking discovery in the study of Amyotrophic Lateral Sclerosis (ALS). Utilizing the advanced gene-editing tool CRISPR and stem cells, the team identified common mitochondrial dysfunctions in nerve cells affected by various ALS-related gene mutations, a revelation that could transform treatment approaches for this debilitating neurological disease.
Eva Hedlund, a professor of neurochemistry at Stockholm University, and her team discovered that mitochondrial issues in motor neurons appear long before other signs of the disease manifest.
“We show that the nerve cells, termed motor neurons, that will eventually die in ALS have problems soon after they are formed. We saw the earliest sign of problems in the cell’s energy factories, the mitochondria, and also in how they are transported out into the nerve cells’ long processes where there is a great need for them and the energy they produce,” Hedlund, who led the research alongside Marc-David Ruepp of the UK Dementia Research Institute at King’s College London, said in a news release.
The findings, published in the journal Nature Communications, mark a significant shift in understanding ALS’s progression.
Historically, it was believed that mislocalization of proteins within cells was the initial step in disease development. However, this new study points to mitochondrial dysfunction as an early indicator, common across different gene mutations causing ALS.
The implications are profound, suggesting new avenues for drug targeting.
“This means that there are common factors that could be targeted with drugs, regardless of the cause of the disease,” Hedlund added.
The research demonstrated that whether mutated proteins were correctly or incorrectly located within cells, mitochondrial dysfunction persisted. This discovery challenges previous notions that protein mislocalization was the primary early event in ALS pathology.
“Until now, it has been believed that it is the change where the proteins are within the cells, called mislocalization, that occurs first,” Ruepp said in the news release.
To reach these conclusions, the researchers employed CRISPR/Cas9 to introduce ALS-causing mutations into human induced pluripotent stem cells (iPSCs). These cells were then differentiated into motor neurons and interneurons. Using single-cell RNA sequencing, they were able to identify a distinct disease signature specific to motor neurons affected by ALS mutations.
“In the data we obtained, we identified a common disease signature across all ALS-causing mutations, which was unique to motor neurons and thus did not arise in resistant neurons,” added first author Christoph Schweingruber, a research fellow at King’s College London.
The team’s work reveals potential strategies for early intervention. As Hedlund explains, understanding the early failure points in motor neurons and their impacts on cellular energy and communication could guide the development of treatments aimed at preserving neuron-muscle communication and preventing neuron death.
“By making various CRISPR mutations in the ALS-causing FUS-gene, we have now been able to show for the first time that most errors arising are caused by a new toxic property of the protein, not by a loss of function,” Schweingruber added.
The research highlights the critical role of mitochondria and their transport within nerve cells, particularly to axons, where energy demands are highest. Disruption in this transport mechanism could underlie the synaptic failures observed in ALS patients.
“Without them, the nerve cells do not have enough energy to communicate properly with other cells,” Hedlund added.
In summary, these pivotal discoveries not only deepen our understanding of ALS but also open new pathways for therapeutic development. With ongoing research, the team aims to further demystify the disease’s early stages and identify targets for novel treatments.
Source: Stockholm University