Wednesday, 7 October 2015

Understanding energy generation, the holy grail of aging research in motor neurone disease



As a scientist working on MND I often get asked to describe what a typical day at work is like. Now the great thing about a career in science (if you are lucky like me!) is that every day tends to be different, it certainly is not your typical 9 to 5 office job (no offense to those who have typical 9-5 office jobs). 

But today was especially unique as I found out that my translational neuroscience MSc student, Laura Francis, came top of her class and was awarded both a distinction and the Johnathan Stone Prize. I was really pleased for her as she worked really hard, generated some interesting data and more importantly did not complain when I turned the volume up on the radio when Oasis came on. I had a slightly depressing moment though when I realised that Laura was born the year before I took my GSCE exams, in 1993. 

Laura is part of an up and coming new wave of young, enthusiastic scientists with bags of energy. I thought I was still part of that group, then I looked in the mirror and realised I had grown into a rubber faced 37 year old bloke with two kids, a dog and a DIY obsessed wife. Give it 15 years, I told myself over my fifth cup of morning coffee, she may not be as sprightly in the mornings then! Aging can catch up on you at any moment, as the great Kevin Keegan once said “those 32 and 33 year old players will be 34 and 35 in two years’ time at the World Cup if they’re not careful!”
 

Aging affects the body in many ways. Interestingly at a cellular level, the ability to make energy to help the cells in your body function properly becomes less efficient with age. This means as you get older your cells struggle more and more to take in fuel from the diet and turn it into fuel for the cell. This loss of function is also observed in people affected by MND even those who are middle aged and not classed as “old”, whatever that means? Many researchers in the field believe that MND may even be an early aging disease. 

Part of my work is looking to see how MND affects the ability of the cell to make energy. The energy generation system in cells is a complex network of interlinking pathways. These pathways are in balance and they work together to make energy, one pathway can upregulate its function to compensate for other pathway being downregulated and vice versa. 

I have a theory that in a healthy person there is a certain amount of flexibility in the metabolic pathways that is lost for some reason in MND. We have just recently published a paper in Neurobiology of Aging, where we took skin cells from patients and healthy controls and assessed the function of the two main energy generating pathways in the cell using a very cool piece of kit called a Seahorse bioanalyser kindly donated by Neurocare.

A dashing young scientist using the Seahorse bioanalyser

The bioanalyser measures the oxygen taken in by the cell and the hydrogen ions pumped out of the cell. Oxygen consumption predominantly originates in a part of the cell called the mitochondria which consume oxygen to produce energy. Hydrogen ions are a byproduct of glucose being taken into the cell from the diet and metabolised to produce energy. We found that skin cells from healthy control cases increased their mitochondrial oxygen consumption and decreased their hydrogen ion production with age. When you fluorescently labelled the mitochondria you could see them becoming more interconnected with each other with age to allow this increase in oxygen consumption to occur. This networking of the mitochondria is critical for their function.

Interconnected mitochondria in the skin cell of a healthy control case.
Interestingly the skin cells from MND patients lost this ability to interconnect their mitochondria and increase oxygen consumption. However, they did have the ability to increase their glucose consumption to cope with the defect in mitochondrial function. This metabolic flexibility may be one of the reasons that the skin cells don’t die in MND unlike cells in the central nervous system (CNS) such as motor neurones. We are now using human astrocytes reprogrammed from the skin cells of MND patients by stem cell technology to identify whether this metabolic flexibility is also evident in the CNS cells.

If we can understand why at a metabolic level aging is a risk factor for MND, we can develop rational approaches for nutritional supplementation to support healthy neuron metabolism. Then hopefully people who develop MND at 32 or 33 will reach 34 or 35 in two years’ time if they're careful, right Kevin?

 

Reference:
Allen SP, Duffy LM, Shaw PJ, Grierson AJ. Altered age-related changes in bioenergetic properties and mitochondrial morphology in fibroblasts from sporadic amyotrophic lateral sclerosis patients. Neurobiol Aging. 2015 Oct;36(10):2893-903. doi: 10.1016/j.neurobiolaging.2015.07.013.


By Dr Scott Allen 



Scott is a senior researcher in Prof Pam Shaw's group. His research focus is how MND affects the major energy generation pathways in the central nervous system and how the disease affects the metabolic response to aging. You can view his profile on Researchgate and LinkedIn to see links to his recent publications.

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