A. Vagnoni & S. Bullock
Study reverses effects of aging on the transport system of neurons in a fly model system
29 Mar 2018
A study has found that a characteristic of aging in neurons – reduced transport through the cell – can be boosted in later life. The finding that feeding the flies a messenger molecule, cAMP, reinvigorates transport in older neurons could aid our understanding of how the function of neurons declines with age and in dementia.
The scientists, from the MRC Laboratory for Molecular Biology (LMB), caution that while this unique fly model helps us to understand transport inside the nerve cells of a living animal, it is not yet known how these findings will apply to human neurons, and that declining transport is only one aspect of neuronal aging.
Transport within nerve cells is driven by ‘molecular motors’, remarkable proteins that bind to cellular components and drag them to their destination by walking along filaments in the cell. This process is similar to a rail network, with the motors acting as engines that haul cargos along on tracks.
Previous research has shown that during ageing there is a decline in the transport system in neurons and this has been linked to the development of dementia and other neurodegenerative diseases.
The new study, published in Current Biology, investigated whether it is possible to reverse the age-related decline in the transport system by focusing on the transport of mitochondria – the power plants of the cell.
Mitochondria need to be moved along the long nerve cells by motors to ensure an efficient energy supply throughout the cell. Also, as the mitochondria age, they need to be shuttled to recycling stations in the cell where they can be recycled and replaced.
The researchers discovered a five-fold decrease in the transport of mitochondria in ‘old’ flies (30 days old) compared with ‘young’ flies (two days old). They also found that the level of a key motor protein, kinesin, declines with age.
When they fed old flies cAMP, which activates a protein called PKA, the level of the kinesin motor increased and transport levels were restored to that observed in young flies. They corroborated the results by manipulating the PKA and kinesin genes in old flies.
Dr Alessio Vagnoni, lead author of the paper who was at the MRC LMB, and who recently established his own group at King’s College London, said: “It is exciting to find that the age-dependent decline of a process that is critical for the function of neurons can be suppressed. It is very interesting that we are able to restore transport in older fruit flies’ neurons by feeding them a small molecule. We share many genes in common with the fruit flies and modelling the ageing process in these animals is quicker than in rodents, leading to faster discoveries. We hope that by finding strategies to suppress age-dependent cellular dysfunctions in fruit flies, we can help direct research into neurodegeneration in human neurons.”
Dr Simon Bullock, the senior author on the paper from the MRC LMB, said: “There is evidence that some of the proteins we studied are affected in post-mortem brains of individuals affected by Alzheimer’s disease. Our work opens new avenues for understanding how transport in nerves contributes to aging and dementia. However, it is important to emphasise that our study did not directly investigate ageing or degeneration in human neurons. We have a long way to go before we understand if this is directly relevant to neurodegeneration in humans, but this is certainly an interesting lead.”
The study is part of a project to develop better models to advance our understanding of aging, neurodegeneration and dementia, and to reduce the use of rodent models for this purpose. The researchers developed a unique, non-invasive system using translucent fruit fly wings, which enabled them to study transport inside nerve cells of a living animal.
Dr Nathan Richardson, Head of Molecular and Cellular Medicine at the MRC, said: “It’s great to see how, through co-funding with NC3Rs, our researchers have exploited the fly as a model to reveal new insights into neuronal cell function, how this declines with age and how it can be reversed in the lab. This will provide valuable contributions to our mechanistic understanding of neurodegeneration.”
The study was funded by the MRC, a National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) David Sainsbury Fellowship and a Van Geest Fellowship in Dementia and Neurodegeneration.
This paper is available on Europe PMC.