Scientists at the Tata Institute of Fundamental Research (TIFR) have provided a fruit fly model for studying how drugs that block the degradation of brain chemicals – neurotransmitters – could slow down the progression of dementia and neurodegenerative disorders such as the Alzheimer’s disease.
A three-member TIFR team, in collaboration with members of the US-based Jungers Center for Neurosciences Research, Oregon Health Sciences University, and Sophia College, Mumbai, has found that an imbalance in the supply of two enzymes – Rab4 and acetylcholinesterase – from the neuronal cells (nerve cells) to the synapse may degrade the brain.
Neurons use electrical signals to communicate with each other through the synapses, which are the junctions between two neurons, in a brain. Synapses are vital for passing on information from one nerve cell to another and keep the brain alive. Electrical signals, on reaching the end of the neuron and before moving on to the next neuron, get converted into chemical signals at the synapse. Loss of synaptic functions in the human brain causes many progressive neurodegenerative disorders such as Alzheimer’s disease.
Using Drosophila melanogaster – a common fruit fly that is widely used in biological research – the team found that both Rab4 and acetylcholinesterase are carried by the same type of molecular motor proteins called Kinesin, which acts like a locomotive and controls the supply of enzymes to the synapse in an automated manner.
“Actions of these two enzymes seem to oppose each other in synapse formation. The synapse disappears when either less acetylcholinesterase or more Rab4 are supplied,” said Krishanu Ray, professor at the Department of Biological Sciences, TIFR. “Our future studies would be focused on looking at how kinesins make the synapses appear and disappear in the fly brain, and their impact on the behaviour of fruit flies.”
Researchers said while some drugs are given to patients to alleviate the symptoms of neurodegenerative disorders, there is little understanding of how they work on the brain. “We have established a cost-effective experimental system using fruit flies to test how inhibitors of acetylcholinesterase could improve the brain function. We got a small unexpected result that more supply of an enzyme can be detrimental for brain function that wasn’t thought of before,” said Ray.
Research by others had shown that over-function of acetylcholinesterase is linked with accentuating the symptoms of Alzheimer’s disease. At the same time, loss of acetylcholinesterase activity suppresses neural growth and synapse formation in the brain.
Simply put, it means over the function of this enzyme will make the synapses work for a shorter period which will lead to disruption of information transfer, and that can induce progression of neurodegeneration. Thus, both the loss and gain of acetylcholinesterase activity at the synapse is likely to speed up the progression of certain neurodegenerative diseases. “For instance, the onset of Alzheimer’s diseases could be advanced. Instead of memory loss at 80 years, it can set in at 40 years or 60 years,” said Ray.
As for the enzyme Rab4, the team was surprised at their find. “An over-function of Rab4 reduced the synapses whereas under-function increased them and it was reflected in the crawling behaviour of the larva. This was astounding as previously it was shown that the activity of this enzyme was required for the growth of the neuron,” said Swagata Dey, co-investigator, TIFR.
Ray added, “We found that it is the chemical competition between two Kinesin motor proteins that maintains the balance of enzymes at the synapse. As a result, the right amount of synapses is formed. If this balance is lost, either more or fewer synapses will form causing the brain to degrade.”