New Fly Model To Study Motor Neuron Degeneration, ALS

Researchers at the University of Massachusetts Medical School in the United States and the Babraham Institute in the United Kingdom recently revealed a new fly model to study motor neuron degeneration. The study was published in the journal Current Biology and is entitled “Age-Dependent TDP-43-Mediated Motor Neuron Degeneration Requires GSK3, hat-trick, and xmas-2”.

Motor neuron degeneration affects the cells responsible for the control of voluntary muscle movements such as walking, speaking, swallowing and even breathing. Motor neuron diseases can cause increasing disability and, eventually, death.

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease that affects the motor neuron system, and is characterized by the gradual degeneration and atrophy of motor neurons in the brain and spinal cord. ALS patients may become totally paralyzed and the majority dies due to respiratory failure within two to five years after diagnosis. It is estimated that there are 30,000 American ALS patients, and that approximately 5,600 individuals are diagnosed every year, with currently no cure for the disease.

In the study, researchers report the development of a new model to study neurodegeneration based on the common fruit fly (Drosophila melanogaster), specifically focusing on the neurons in the fly’s leg.

Using their model, the team investigated a protein called TDP-43, which is known to have a central role in ALS development. The team reported that over-expression of TDP-43 in the fly leg triggered neurodegeneration. By exposing these flies to a mutagen and searching for offspring with reduced neurodegeneration, researchers were able to identify three genes that possibly mediated the effects of TDP-43: shaggy/GSK3, hat-trick and xmas-2. While the first one had already been associated to neurodegeneration, the latter two were novel discoveries in the neurodegeneration field.

“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.” said the study’s lead author Dr. Jemeen Sreedharan in a news release.

The research team concluded that their new model using the fly’s leg is a valuable tool in the study of neurodegenerative disorders, including ALS and other motor neuron diseases (MND). Regarding TDP-43, the team reported that mutations in the gene lead to age-dependent neurodegeneration of adult motor neurons, and that the loss of GSK3, hat-trick, or xmas-2 can suppress TDP-43’s negative impact.

“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.” concluded the Director of Research Development at the Motor Neurone Disease Association Dr. Brian Dickie.