A study conducted by researchers at the Euan MacDonald Centre at the University of Edinburgh has shed light on how improving the function of mitochondria – the power supply of nerve cells – could be a potential treatment for motor neurone disease, paper published this week in the journal, Acta Neuropathologica (2021). This study paves the way for the generation of novel therapies targeted at boosting energy levels in mitochondria in MND.
Research was led by Dr Arpan Mehta (pictured), our Lady Edith Wolfson Clinical Fellow jointly funded in partnership with the MRC, supervised by Professor Siddharthan Chandran and Dr Bhuvaneish Selvaraj.
The key brain cells affected in MND are the motor neurons that allow us to move, eat and breathe. They represent the longest cells in the human body, with over 90% of the cell made up by long, thin processes called axons that can extend for up to a metre long to connect from our spine to our muscles.
Arpan’s PhD was focused on unravelling the mechanisms leading to defective axons in people with the most common genetic cause of ALS/MND.
The researchers used stem cells derived from people with the C9orf72 mutation that causes both ALS and frontotemporal dementia to generate motor neuron cells ‘in a dish’ to study in the lab.
They found that their axons were shorter than in healthy cells and that transport of mitochondria, the cell’s energy source and essential for the regulation of metabolic pathways and cell survival, that normally move up and down the axons, was impaired. For the first time, they discovered that this is caused by defective energy supply from mitochondria and that by boosting the mitochondria the axon reverted to normal. Time lapse films below show mitochondria travelling along an axon in a motor neuron (nerve cell):Film 1a – a healthy motor neuron: Film 1b – a damaged motor neuron with the C9orf72 gene: Film 2 – a damaged motor neuron with the C9orf72 gene after boosting the mitochondria:
These findings were further supported by examining human post-mortem spinal cord tissue from people with MND who had kindly donated their tissue.
“The importance of the axon in motor nerve cells cannot be overstated, which led us to focus on the causes of axonal dysfunction.
“Our data provide hope that by restoring the cell’s energy source we can protect the axons and their connection to muscle from degeneration. Work is now underway to identify existing licensed drugs that can boost mitochondrial function and repair the motor neurons. This will then pave the way to test them in clinical trials.”– Dr Arpan Mehta, MRC/MND Association Lady Edith Wolfson Clinical Fellow
Dr Brian Dickie, Director of Research Development at the MND Association, said: “Neurons are the most energy hungry cells in the body and the unique structure of motor neurons in particular means that they need to closely regulate and maintain their energy production. These new findings indicate that a deficiency is occurring, but it is a deficiency that also offers a potential therapeutic target.”
Although the research focused on people with the most common genetic cause of MND, the researchers are hopeful that the results will apply to wider forms of the disease, such as sporadic ALS.
The results of the study are now being used to look for existing drugs that can boost mitochondrial function and could be repurposed to treat MND. Thousands of potential compounds will need to be screened before one is recommended for large-scale clinical trials to test its safety and efficacy.
For more information, please see the FAQs that Dr Mehta has prepared in response to the media attention surrounding this research. Thank you.
The research was funded by the Medical Research Council, Motor Neurone Disease Association, Euan MacDonald Centre for MND Research, My Name’5 Doddie Foundation, UK Dementia Research Institute and Anne Rowling Regenerative Neurology Clinic.
Mehta, A.R., Gregory, J.M., Dando, O. et al. Mitochondrial bioenergetic deficits in C9orf72 amyotrophic lateral sclerosis motor neurons cause dysfunctional axonal homeostasis. Acta Neuropathol (2021). https://link.springer.com/article/10.1007/s00401-020-02252-5
Related blogs posts:
- Focusing on mitochondria – a potential target for early MND treatment?
- How our Lady Edith Wolfson Fellowship launched Dr Arpan Mehta’s career
- The FUS with faulty mitochondria – the powerhouse of the cell
Featured image: Euan MacDonald visits Dr Mehta at the Scottish Centre for Regenerative Medicine at the University of Edinburgh (MAVERICK PHOTO AGENCY).