Boosting brain immune cell waste clearance could provide new drug target for MND
Apr 2023: A new research study has revealed that the essential waste clearance role within 'microglia', the brain’s resident immune cells, is impaired in MND.
Accumulating evidence indicates that cells in the brain called microglia play an important role in maintaining the health of motor neurons.
In this study, Euan MacDonald Centre researchers from the UK Dementia Research Institute at Edinburgh, with colleagues at the MRC Protein Phosphorylation Unit at the University of Dundee, used state-of-the-art stem cell techniques to generate microglia from people with the most common genetic cause of MND (the C9orf72 mutation).
Impaired waste removal
The team set out to investigate how these brain immune cells may contribute to the death of motor neurons, finding that the essential waste clearance role within microglia, a process also known as autophagy, was impaired. This was also the case when they tested the function of immune cells taken from blood samples from people with MND with the same C9orf72 mutation.
Importantly, the researchers observed that the impaired waste clearance led to the build-up of toxic chemicals within the microglia that spilled over into the cellular environment, leading to motor neuron death.
By boosting waste clearance in microglia, in this laboratory situation, the team were able to show that they could prevent this.
Dr Poulomi Banerjee, first author of this study, said:
These exciting results highlight for the first time that dysregulation in microglial cells can be overcome by boosting autophagy and thereby rescue the motor neuron pathology seen in MND.
Microglia in action
This short movie shows microglial cells generated from stem cells in a dish in a lab can 'gobble up' fluorescent beads. This demonstrates their role in cellular 'waste disposal'.
Next steps for the research
This new research gives a suggestion about what might be happening in the brain cells of people with MND, and causing motor neurons to degenerate. However, it is early days.
Next, the researchers plan to carry out further detailed laboratory studies on the role of microglia in MND, with the ultimate aim of identifying new drugs that could be tested in clinical trials.
This study provides hope for the development of new therapies for people with MND targeted at glial cells. However, it is important to recognise that a breakthrough in the laboratory takes time to translate to the clinic. This is now our priority.
Professor Siddharthan Chandran
The study was published in the journal Science Advances.
In the image, the immune cells (microglia) are highlighted in green; spinal nerve cells are highlighted in pink and neuronal projections in grey.
Related links
Read the scientific article (freely available): Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration. DOI: 10.1126/sciadv.abq0651