Scientists have identified a potential drug molecule1 that ramps up the ability of a diseased cell to clean itself. The small molecule called 6-Bio cleans up toxic protein clumps in brain cells. Protein clumps are known to lead to disorders such as Parkinson disease and the finding may hold therapeutic promise.
Toxic protein aggregates accumulate over a period of time in brain cells for various reasons. These aggregates destroy brain cells and may result in neurodegenerative diseases. In Parkinson disease, where the main physical symptom is poor motor coordination, sufferers’ cells are congested with clumps of protein. Healthy cells are usually able to clear these aggregates, but in neurodegenerative diseases, the clearance mechanism — autophagy — is ineffective.
Researchers say there might be a way to restore this essential intracellular quality control mechanism. They found that the small molecule 6-Bio can clear accumulated cellular junk and avert further neuronal loss.
“6-Bio has potent autophagy-inducing ability, which helps cells clear these protein aggregates,” said Ravi Manjithaya, corresponding author of the study and an Assistant Professor at the Molecular Biology and Genetics Unit of the Jawaharlal Nehru Centre for Advanced Scientific Research (JNCASR) in Bangalore.
In the past several years, autophagy has been linked to many maladies, ranging from cancer to Crohn’s disease. The autophagy process not only cleans up cell debris but also recycles the waste to supply energy to the cell.
While investigating the rate of autophagy, Manjithaya’s group observed a brake system that regulates the normal autophagy process. In the presence of 6-Bio, “it’s like taking your leg off the brake and pressing down the accelerator,” Manjithaya said.
Discovery
Using yeast, lead author of the study S. N. Suresh screened 1280 pharmacologically active compounds to identify ones that help yeast cells destroy protein aggregates. Suresh found that 6-Bio facilitated yeast cell survival by promoting autophagy.
The group then tested 6-Bio in a mouse model of Parkinson’s disease, and in human neuronal cells. Notably, 6-Bio was able to clear SNCA/α-synuclein clumps — widely known for their role in Alzheimer’s disease — by inducing autophagy.
The group zeroed in on Glycogen Synthase Kinase 3 Beta (GSK3β), a protein involved in cellular processes ranging from energy metabolism to neuronal cell development. Changes in this protein have been linked to modified Parkinson’s risk. The group found that GSK3β puts the “brakes on autophagy”, slowing down the cleaning process. Adding 6-Bio removed GSK3β inhibition, allowing for the clean-up of protein clumps.
6-Bio belongs to a class of indirubin oximes, biologically active compounds with a high affinity for GSK3β. The molecule latches onto GSK3β, freeing autophagosomes to do their job.
6-Bio still has a long way to go before becoming a drug, including testing to see whether it could reach the human brain. But by employing a chemical genetics approach, Manjithaya thinks the group has made headway into understanding autophagy regulation.
“Any drug that targets this braking mechanism should be able to induce more autophagy and thus help clear off protein clumps — a potential therapeutic option for neurodegenerative disorders such as Parkinson’s and Alzheimer’s, which currently have no cure,” he said.
