Increasing the levels of a neurotransmitter-generating brain enzyme that is in short supply in paralysis disorders restored movement in a fly model of ALS, an Italian study shows.
Bolstering the Gad1 enzyme’s levels also led to the return of a pre-disease pattern of nerve cell organization, the researchers said.
The findings could pave the way to a better understanding of the molecular mechanisms behind ALS-associated paralysis, they added.
They titled their study, which appeared in Scientific Reports, “Downregulation of glutamic acid decarboxylase in Drosophila TDP- 43-null brains provokes paralysis by affecting the organization of the neuromuscular synapses.”
Teams from the International Center for Genetic Engineering and Biotechnology and the University of Milan conducted the research.
ALS is characterized by progressive muscle paralysis stemming from degeneration of nerve cells and the spinal cord. Several animal studies have linked defects in the TDP-43 protein to ALS symptoms.
Flies have a protein called TBPH whose function is similar to TDP-43. It is essential to preventing ALS-associated movement problems, researchers said.
Scientists disagree about what causes ALS. Studies in flies suggest that it’s a defective version of TBPH rather than nerve cell dysfunction.
To try to shed light on the matter, the Italian scientists looked at proteins in the heads of flies with a mutant TBPH gene — which generates a faulty version of TBPH protein — and in the heads of healthy flies.
They discovered that the mutant flies had lower levels of Gad1. When they increased the enzyme’s levels, the flies regained their movement and ability to send messages between nerve cells.
The team also found high concentrations of another neurotransmitter, glutamate, outside nerve cells. High levels of glutamate in the brain are toxic and can cause nerve cells to become over-active.
Blocking the glutamate receptors on the mutant flies’ nerve cells led to the cells’ activity returning to normal, the researchers said.
Importantly, the team found a similar relationship between TDP-43 and Gad1 in humans. This suggested their findings in flies could lead to research that increases scientists’ understanding of the molecular mechanisms behind ALS.
The team said it found “defects in Gad1 levels associated with pathological modifications in TDP-43” in movement-related nerve cells from ALS patients.