New groundbreaking research conducted by scientists at the Francis Crick Institute and UCL has shed light on the complexity of motor neuron disease (MND), commonly known as amyotrophic lateral sclerosis (ALS). This devastating condition leads to rapid paralysis by affecting motor neurons, and treatment options have been limited.
Previous knowledge focused on a few proteins, especially TDP-43, being found in unexpected locations within ALS-affected nerve cells. However, the latest study, published in Neuron, has revealed a much wider issue of “mislocalization” of hundreds of proteins and mRNA molecules in these cells. This mislocalization affects essential proteins involved in RNA binding and even extends to mRNA molecules, which deliver instructions to create proteins.
To understand this phenomenon better, the researchers used stem cells from patients with ALS-causing mutations and created motor neurons. They observed that in ALS cells, numerous proteins and mRNAs were found in the wrong compartments of the cell (nucleus and cytoplasm) compared to healthy cells, suggesting potential transport issues within the cell.
Additionally, they noticed that mislocated mRNAs and proteins interacted more with each other, leading to a domino effect of mislocalization.
Remarkably, a drug called ML240, which inhibits the VCP enzyme, partially improved the mislocalization of proteins and mRNAs. It also had beneficial effects on cell function, reducing DNA damage.
The lead researchers expressed hope that these findings could pave the way for new research and potential therapies for ALS, offering a glimmer of hope for patients suffering from this devastating condition. They plan to investigate protein and mRNA location in other ALS genetic backgrounds and explore further the potential of VCP inhibitors as a therapy for ALS.
However, it’s important to note that there is still much work to be done before these findings can be applied clinically. ML240 has not yet been tested in animals, and additional chemical changes may be needed to ensure it enters nerve cells without causing side effects. Nevertheless, this research marks a significant step forward in understanding and potentially treating ALS.
Source: The Francis Crick Institute