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IIT-Hyderabad researchers make headway in potential treatment of ALS

The researchers have identified a molecule called AIM4 and the mechanism through which it could help in the treatment of the disease. ALS is a rare and debilitating neurodegenerative disorder that affects the voluntary movement of the muscles and can even lead to paralysis or death.

, ET Bureau|
Last Updated: Feb 06, 2020, 08.09 PM IST
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The research was performed by a team lead by Patel, Sandeep Singh and Rajakumara Eerappa, faculty from the Department of Biotechnology, IIT Hyderabad, and Prabushankar, Department of Chemistry, IIT Hyderabad.
NEW DELHI: Researchers from the Indian Institute of technology, Hyderabad have made potential headway in the treatment of ALS (Amyotrophic Lateral Sclerosis), also known as Lou Gehrig's disease.

The researchers have identified a molecule called AIM4 and the mechanism through which it could help in the treatment of the disease.

ALS is a rare and debilitating neurodegenerative disorder that affects the voluntary movement of the muscles and can even lead to paralysis or death.

In 2014, an awareness campaign, called the 'ALS Ice Bucket Challenge', that involved people throwing ice water on themselves, and challenging others to do the same, went viral on social media.

ALS happens due to changes in certain changes, that could be triggered by environmental factors like smoking and exposure to toxins, metals or pesticides.

Right now, there is no cure for the disease. The only options available for patients are two drugs that help manage the disease.

The disease is relatively unknown in India although Indians seem to have an earlier onset of this malady compared to people in the West and show longer lasting symptoms and disease progression.

Speaking about the research, Basant Kumar Patel, associate professor, Department of Biotechnology, IIT Hyderabad, said, “One of the causes of ALS is the alterations in the genes that code for a critical protein called TDP-43. The gene alteration modifies the protein, which results in its liquid-liquid phase separation. This phase separation in turn causes the proteins to be deposited on nerve cells, resulting in neurodegeneration.”

In 2016, Patel and G. Prabushankar found a small molecule called ‘AIM4,’ which seemed to be better than the other related molecules that have been studied all around the world, in its ability to inhibit abnormal aggregation of TDP-43 in vitro ALS disease model systems. The scientists proceeded to analyse this molecule and study its action on TDP-43, to predict how it would potentially inhibit the deposition of the protein in nerve cells. The results of the research were published in the International Journal of Biological Macromolecules.

Patel added, “We have shown that AIM4 prevents liquid-liquid phase separation of the modified protein, TDP-43-A315T. By this, AIM4 prevents aggregation of the protein and may potentially prevent the deposition on neurons.”

The research group compared the ability of AIM4 to prevent protein phase separation with that of other molecules such as Dimebon. Dimebon is an antihistamine that was studied for treatment of neurodegenerative disorders by an American pharmaceutical company but failed clinical trials. AIM4 was better than such earlier molecules in preventing protein phase separation, found the researchers.

The research team has also discovered through computational studies that AIM4 has specific binding site on this protein and binding energy calculations have shown that the bond between AIM4 and the mutant protein is energetically favourable, which makes it a promising drug for potential treatment of ALS.

“This work is an important step forward in the area of therapeutics of the neurodegenerative disease ALS as current options for ALS are minimal or even non-existent”, said Patel.

The research was performed by a team lead by Patel, Sandeep Singh and Rajakumara Eerappa, faculty from the Department of Biotechnology, IIT Hyderabad, and Prabushankar, Department of Chemistry, IIT Hyderabad.

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