Health & Medicine, UK (Commonwealth Union) – Scientists from the Francis Crick Institute along with the University College London (UCL) have demonstrated that 100s of proteins and mRNA molecules are situated in the incorrect place in nerve cells impacted by motor neurone disease (MND), also referred to as amyotrophic lateral sclerosis (ALS).
ALS is a rapidly progressive and devastating disease that leads to paralysis by affecting motor neurons, offering limited treatment options. Previously, scientists acknowledged the presence of a few proteins, notably TDP-43, in unexpected locations within ALS nerve cells.
However, groundbreaking research recently published in Neuron reveals a much broader issue. This phenomenon of ‘mislocalisation’ goes beyond a few proteins and significantly impacts numerous others, particularly those involved in RNA binding. Even the mRNAs, responsible for delivering instructions from the nucleus DNA to produce proteins, experience mislocalisation.
To conduct this study, researchers utilized stem cells from ALS patients to generate motor neurons bearing mutations in the TARDBP and VCP genes, known to be a factor in ALS. By isolating the cell’s two main compartments, the nucleus and cytoplasm, they analyzed all the mRNA and protein present in each. The results unveiled that in ALS cells, hundreds of mRNAs and proteins were improperly located compared to their healthy counterparts. This discovery sheds new light on the complexity of ALS and may open doors to potential therapeutic interventions.
During their investigation, the researchers observed a noteworthy phenomenon: certain proteins and mRNAs were shifting from their usual location in the cell’s nucleus, which acts as the ‘control center,’ to the cytoplasm, the ‘body’ of the cell, or vice versa. This observation pointed towards possible transport issues within the cell.
Furthermore, the research team noticed that these mislocated mRNAs and proteins exhibited a higher level of interaction with each other, in comparison to their counterparts correctly positioned within the cell. This led the researchers to speculate that as these mRNAs and proteins mislocalise, they might influence and pull each other along, setting off a domino effect within the cellular environment.
Oliver Ziff, clinician scientist at the Crick as well as the University College London Hospitals NHS Foundation Trust (UCLH), says “We were surprised to see the extent of the mislocalisation, particularly for mRNAs, as this hasn’t been reported before. The goal now is to find where this problem starts and there are many intriguing possibilities – one being a breakdown in the transport between the nucleus and cytoplasm. “
He further indicated that the research was an exceptional team effort, and that he was extremely appreciative of his colleagues, specifically the co-first authors, Drs Jasmine Harley, Yiran Wang, as well as Jacob Neeves.
Remarkably, the researchers discovered that the mislocalisation of proteins and mRNAs showed some improvement when treated with a drug known as ML240. This drug works by inhibiting the action of the VCP enzyme. Interestingly, blocking this enzyme not only had a positive impact on the mislocalisation issue but also resulted in other beneficial effects on cell function, notably reducing the level of DNA damage. This finding opens up promising possibilities for potential therapeutic approaches in managing ALS and addressing its underlying cellular mechanisms.
Rickie Patani, who is a senior group leader from the Human Stem Cells and Neurodegeneration Laboratory at the Crick, a professor at UCL, a consultant neurologist at the National Hospital for Neurology, as well as an MRC Senior Clinical Fellow, expressed his deep concern about the lack of impactful treatments for ALS patients that he encounters in his practice. The current research marks a significant shift in our understanding of ALS causation. It goes beyond the involvement of only a few proteins with abnormal movement; instead, it reveals the unusual localisation of hundreds of proteins and mRNAs as a key factor in the disease. This groundbreaking insight opens up new and promising avenues for further research and the development of potential therapies to combat ALS.
