Novel fly model of motor neuron degeneration provides new avenues for exploration in humans
Researchers at the Babraham Institute and University of Massachusetts Medical School in the United States have developed a new model to study motor neuron degeneration and have used this to identify three genes involved in the neurodegeneration process. These findings could have relevance for understanding the progression of amyotrophic lateral sclerosis (ALS) and other forms of motor neuron disease (MND). ALS is the most common form of adult-onset motor neuron disease and kills over 1,200 people a year in the UK.
The researchers developed a new model to study neurodegeneration in the common fruit fly (Drosophila melanogaster). In contrast to other methods used to study neurodegeneration such as looking at changes in eye morphology or studying larval stages, the researchers focused their attention on studying the neurons in a fruit fly’s leg. Using the leg allows the detailed study of a single motor neuron, the nerve cell involved in passing signals from the brain to a muscle. Compared to studying larval stages, the model also permits genuine ageing studies as changes in neurons can be observed in flies of different ages. The adult fruit fly can live for over two months in the lab. Furthermore, the fruit fly also provides the benefits of rapid development (ten days from egg to adult), allowing high-throughput genetic screens.
As described online in Current Biology, the researchers used the new model to study the role of a protein central to the development of ALS called TDP-43. Specifically overexpressing TDP-43 in fly legs caused neurodegeneration. Exposing these flies to a mutagen and looking for offspring showing reduced neurodegeneration allowed the researchers to identify three genes implicated in mediating the effects of TDP-43. One, shaggy/GSK3, was already know to be associated with the neurodegeneration process but two of them, hat-trick and xmas-2, were new discoveries.
Dr Jemeen Sreedharan, Senior Research Fellow in the signalling research programme at the Babraham Institute and lead author on the paper said: “We’re extremely excited about our new approach to using the power of Drosophila genetics. Never before has anyone been able to study adult neurodegeneration in an invertebrate system with such ease. By modelling the earliest stages of ALS (synaptic and axon degeneration) we have identified three intriguing genetic suppressors of degeneration in the fly and are now validating these results in mammalian neuronal cultures. We hope that by using the fly we can accelerate progress towards eventually developing therapies for ALS and other neurodegenerative diseases.”
Brian Dickie, Director of Research Development at the Motor Neurone Disease Association said: “If we can mimic MND in the lab then we can better understand what’s happening to the motor neurones in people living with MND. This is an important foundation for developing treatments for the disease. Having skilled, driven and creative researchers working in the lab is as important as the lab work itself, Jemeen and his peers within the Lady Edith Wolfson Fellowship scheme are really taking MND research from strength to strength.”
Funding support for this research was provided by the Medical Research Council, a Motor Neurone Disease Association Lady Edith Wolfson Fellowship and the Max Rosenfeld Fund. The Babraham Institute receives strategic funding (a total of £28.8M in 2013-14) from the Biotechnology and Biological Sciences Research Council (BBSRC).
Jemeen Sreedharan, senior research fellow, Coleman group, Signalling programme
Shown on the left is a low magnification image of a fly leg in which all the motor neurons are visualised by expression of membrane-bound green fluorescent protein. Sensory neurons are also visible. The right hand panels are higher magnification images of motor neuronal synapses (neuromuscular junctions) within the fly leg. The top panel is from a control (wild type) fly and demonstrates beautifully the regular and dense arrangement of synapses, which are seen as dots. The panel below shows the degeneration caused by overexpression of TDP-43, a protein central to the pathogenesis of ALS.
Animal research statement:
As a publicly funded research institute, the Babraham Institute is committed to engagement and transparency in all aspects of its research. The research presented here used fruit flies (Drosophila melanogaster) and is an example of how research at the Babraham Institute uses alternatives to animals whenever possible in accordance with the principles of the 3Rs: Replacement, Reduction and Refinement.
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Sreedharan et al. (2015) Age-dependent TDP-43-mediated motor neuron degeneration requires GSK3, hat-trick and xmas-2. Current Biology (in press). Subscription required to view full text.