A new study by researchers at the Indian Institute of Technology, Kanpur has identified a small molecule drug which shows therapeutic promise against Huntington’s disease, a fatal neurodegenerative disorder. The molecule prevents the formation of protein clumps or aggregates which are detrimental for the health of neurons.
Huntington’s disease is a debilitating neurodegenerative condition caused by the abnormal activity of the huntingtin gene, which leads to the build-up of unwanted proteins in brain cells. A recent study has inched a step closer in the attempt to find a remedy for this incurable condition.
An international team of Indian scientists, led by Ashwani Kumar Thakur from the Indian Institute of Technology (IIT), Kanpur, report that a molecule called Arginine Ethyl Ester (AEE) exhibits potential in inhibiting huntingtin protein aggregation. The molecule is a derivative of arginine, a natural amino acid found in the body.
Huntington’s Disease (HD) is an inherited genetic disorder affecting nearly one in every 10000 to 30000 individuals. The symptoms develop gradually, characterised by uncontrolled movements, depression, and inability to perform locomotor functions like walking, talking and swallowing, eventually killing the patient.
The huntingtin gene (which produces the huntingtin protein) contains a chain of basic DNA building blocks called CAG (Cytosine, Adenine and Guanine). However, a mutation in the huntingtin gene gives rise to a flawed process wherein CAG is replicated excessively. These extra CAG repeats form long chains of an amino acid called glutamine in the huntingtin protein, which clump together and form a fibrous tangle. The tangles clog the brain cells and eventually destroy them.
In this study, the team attempted to find out if arginine, a naturally occurring amino acid known to show protein stabilising properties, could help suppress the excessive huntingtin protein. “We found that Arginine tends to break intermolecular hydrogen bonds which are one of the responsible factors for making aggregates of huntingtin protein through glutamine-glutamine interaction,” says Thakur.
While deciphering the mode of action of arginine in suppressing the protein accumulation, the team looked into its derivatives to broaden the scope of availability of therapeutic molecules. Among four such probable candidates, they found that Arginine Ethyl Ester (AEE) was the most suitable. To their surprise, they discovered that AEE was better at suppressing protein aggregates than arginine itself.
Advanced NMR spectroscopy revealed that AEE acts in two ways: it not only breaks intermolecular interactions but also directly binds to one of the parts of the huntingtin protein and blocks a crucial step of clumping. Encouraged by this discovery, the team exhaustively tested AEE to understand how huntingtin fragments change and the accumulated proteins destabilize upon interacting with it.
Thakur’s team then demonstrated the efficacy of the molecule in multiple laboratory models, including neuronal cells, yeast cells, and Drosophila (fruit flies). These models imitate many features of Huntington’s disease; for example, the fruit flies were incapable of movement. In all three models, arginine and AEE delayed protein accumulation, with the derivative performing better than arginine. In the case of the diseased drosophila, the flies regained their locomotion when they were given AEE molecules.
Ravi Yadav, Additional Professor of Neurology and Consultant at the Parkinson’s & Movement Disorders Clinic at the National Institute of Mental Health and Neurosciences, NIMHANS, Bengaluru, says, “Till date, many drugs have been tried in various studies, but none have shown any significant effect. This novel research and the results from the laboratory experiments appear to indicate that Arginine Ethyl Ester (AEE) may have the potential to reduce the aggregation of pathological huntingtin protein in cells.” Yadav was not involved in the study.
The discovery of the molecule is under review for an Indian patent. The team is hopeful that their research will provide a platform for the development of arginine-based treatments for Huntington’s disease in the future. “It will be interesting to see the outcomes of the subsequent phases of experiments — in animal models and beyond. Further studies will validate its use in humans,” adds Yadav.
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