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.
Reference:
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).
Very Very Interesting that for MND
Hi John,
Thank you for taking the time to read the article and your positive comment.
Kind regards,
Research Development Team
Sound s very promising and as time is of the essence of people who are living with I am sure many would like to be taking part in these trials . My husband would Love to take part to stop this horrendous disease taking any more of his valued independence. Only offer the drug Rilozole and that s been the only drug for 25 years and with all the research and funding going on is not bringing further drugs to prevent this horrid degeneration
Dear Sue
Thank you for taking the time to read this blog article and leave a comment. Please take a look at our ‘Take part in research’ page – https://www.mndassociation.org/research/get-involved-in-research/take-part-in-research/ – as this lists details of current trials and studies that your husband might be able to take part in.
Kind regards
Mandy
Dear Mr Tallis
Thank you very much for your support of our research.
With kind regards,
Dr Arpan Mehta
MRC/MND Association Lady Edith Wolfson Clinical Fellow
Euan MacDonald Centre for MND Research, University of Edinburgh
Dear Dr Arpan Mehta
I’m David Langridge I live in Leicestershire I’ve lived with MNDALS for 8 years your Research is very interesting but will it help people who have had MND a long time.
It would be very interesting to hear the abilities of the potential of this to repair Motor Neurons in people with long term MND. I would like to thank you for all your hard work on our behalf.
Dear Mr Langridge
We very much hope that therapies that boost the health of the axonal “cables” of the motor nerves will prove to be beneficial for people with established ALS/MND. We first need to find these medicines (through more laboratory studies) and then test them definitively in clinical trials. But, we believe that the early scientific data are promising.
Thank you for your interest and support.
Kind regards
Dr Arpan Mehta
Fingers crossed and here’s hoping, it can’t come soon enough.
It’s encouraging to read about this breakthrough in the understanding of MND. Fingers, legs, and toes crossed (while I still can 🙂 ) that we don’t have to wait 10 years for an effective treatment.
Good luck and great speed in your research!
Thank you for reading this article and taking the time to comment. All feedback is greatly appreciated.
Research Development Team
This is the most encouraging news I’ve heard since diagnosis – is there a trial going on in the north of England?
Dear Phil,
Thank you for taking the time to read our blog and commenting.
There are several research opportunities advertised on our website, including a clinical trial called TUDCA-ALS: https://www.mndassociation.org/research/get-involved-in-research/take-part-in-research/. Please note, each study will have its own inclusion and exclusion criteria which may mean you are not eligible to take part in some. In the first instance, we recommend that you discuss any opportunities for taking part in research with your neurologist.
There are also studies that, although not clinical trials, will help to improve support to people living with MND and their families, and increase our knowledge and understanding of the disease. Many of these allow for remote participation.
Best wishes,
Research Development Team
Fantastic news on your discovery let’s hope can fast track it