A mechanism behind motor neuron degeneration associated with a rare form of amyotrophic lateral sclerosis (ALS) has been revealed.
Researchers at the Case Western Reserve University (OH, USA) have potentially identified a new target for a rare inherited form of ALS. By using patient-derived induced pluripotent stem cells (iPSCs), the researchers were able to uncover a mechanism that leads to motor neuron damage linked to a specific mutation. Their findings may offer insights into developing potential therapeutic approaches for treating this rare type of ALS and other forms of ALS.
ALS is a common neurodegenerative disease that affects nerve cells in the brain and spinal cord, leading to progressive loss of voluntary muscles control. Despite many research efforts, there are currently no effective treatments that stop or reverse disease progression. Developing effective treatments has been complicated by two key factors: the disease’s unpredictable presentation across patients and the varying degrees to which individuals respond to medications. To gain further insight into the degeneration of nerves cells, the researchers set out to study the mechanism of a rare form of ALS, ALS8.
ALS8 is caused by a mutation (proline-to-serine substitution at position 56 [P56S]) in the vesicle-associated membrane protein-B (VAPB), which is an endoplasmic reticulum protein. This P56S mutation affects the domain (major sperm protein domain) of the VAPB protein that helps the endoplasmic reticulum connect with other cellular proteins and organelles. In turn, this disrupts this essential cellular communication network and how nerve cells respond to stress.
In this study, the team used ALS8-patient-derived iPSCs to grow two versions of motor neuron cells ex vivo: a wild-type VAPB protein and a VAPB protein with the P56S mutation. Using CRISPR-Cas9, they removed the VAPB gene from the patient cells and replaced it with the genes for the wild-type and P56S.
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After the iPSCs differentiated into motor neurons, the team found that the VAPB P56S protein could not bind properly to certain mitochondrial proteins. Next, they examined the endoplasmic reticulum and discovered a decreased connection between the endoplasmic reticulum and the mitochondria in the VAPB P56S motor neurons compared to the wild-type motor neurons. Furthermore, the VAPB P56S motor neurons were more sensitive to cell stress. They exhibited early activation of a stress response pathway – Integrated Stress Pathway (ISR).
Interestingly, ISR is a protective mechanism used to restore cellular homeostasis and ensure cell survival; however, sustained ISR activation impairs cell survival and reduces protein production, damaging motor neurons and contributing to VAPB P56S-associated ALS. Recent studies have suggested that the activation of the integrated stress response pathway could be linked between forms of ALS, as well as a possible therapeutic target for this disease. Helen Cristina Miranda, Associate Professor of genetics and genome sciences, and the team then decided to block the ISR pathway using a drug called ISRIB.
“We also showed that blocking this stress response can reverse damage in the lab, a promising step toward future treatments,” said Miranda. “That’s a promising proof-of-concept for future therapeutic strategies.”
The findings from this study provide insight into the mechanism that drives VAPB P56S-associated ALS by demonstrating how this mutation disrupts endoplasmic reticulum communication, impairs mitochondrial function and activates a stress response pathway that contributes to the degeneration and damage of motor neurons. The findings also identify the ISR as a potential target for VAPB P56S-associated ALS.
Looking ahead, the researchers are hoping to expand their research to investigate ISR as a target for other forms of ALS.
“We are now testing ISR inhibitors in more complex neuromuscular models and exploring how this approach might benefit other ALS subtypes,” commented Miranda.