IIT-H finds molecule to treat rare neurodegenerative disease

Researchers of the Indian Institute of Technology Hyderabad (IIT-H) have found a molecule called “AIM4” that can help in the treatment of a rare and debilitating neurodegenerative disease called “Amyotrophic Lateral Sclerosis” (ALS) also known as “Lou Gehrig’s disease”.

ALS is a neurodegenerative disorder that severely affects voluntary movement of muscles and can lead to paralysis and death. It occurs due to changes in specific genes, which may be triggered by factors such as smoking, exposure to toxins, metals and pesticides.

The results of this research, performed by a team led by Basant Kumar Patel, Sandeep Singh and Rajakumara Eerappa, faculty from the Department of Biotechnology, IIT-H, and Ganesan Prabushankar from the Department of Chemistry, were recently published in the peer-reviewed International Journal of Biological Macromolecules.

The paper has been co-authored by these scientists along with research scholars Amandeep Girdhar, Vidhya Bharathi, Vikas Ramyagya Tiwari, Suman Abhishek, Waghela Deeksha, Usha Saraswat Mahawar and Gembali Raju.

Currently, no drugs are available to cure ALS. The treatment options are limited to two drugs only to manage the condition. Research is ongoing throughout the world to find better drugs that can arrest this disorder and not merely manage the symptoms. Such a research must first identify the causes for the onset of ALS.

“One of the causes of ALS is alterations in 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 proteins to be deposited on nerve cells, resulting in neurodegeneration,” said Basant Kumar Patel, associate professor.

In 2016, Dr. Patel and Prof. 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.

Armed with this knowledge, IIT-H scientists proceeded to analyse this molecule and study its action on TDP-43, to predict how it would potentially inhibit the deposition of protein in nerve cells.

Dr. 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 like Dimebon. Dimebon is an antihistamine that was studied for treatment of neurodegenerative disorders by an American pharmaceutical company but failed clinical trials.

The IIT-H research team found that AIM4 was better than earlier molecules in preventing protein phase separation.

The research team 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 towards an area of therapeutics of the neurodegenerative disease, ALS, as current options for ALS are minimal or even non-existent,” said Dr. Patel.