Manipulation of cell cleansing could help study its role in cancer, neurodegenerative diseases: Study

New Delhi, A cell's automatic waste clearance may now be externally manipulated, potentially helping researchers understand cell cleansing in cancer or Parkinson's disease, where the process is known to go awry, a study has shown.

The study was conducted by researchers at New Delhi's Council of Scientific and Industrial Research -Institute of Genomics and Integrative Biology and National Institute of Immunology, Ashoka University in Sonepat and the US' University of California Los Angeles.

Autophagy is a recycling process whereby a cell clears out or recycles unwanted objects by forming a recycling bin-like cavity called an 'autophagosome'. The "recycling bin" of the cell grows a lining which encloses the cell debris, breaks it down and reuses the components for energy or new growth.

Among the triggers of autophagy, one is intermittent fasting, in which following long hours of fasting, low levels of glucose and amino acids signal the body to conserve energy. 'Phagy' in Greek means 'self-eating'.

The researchers observed the trajectory of the behaviour of a protein 'LC3', involved in autophagy, through simulations and found that it shifts shape upon touching the inner surface of a cell's recycling bin.

A computational analysis of the simulations of the protein LC3, followed up with experiments, revealed that for two mutant shapes, autophagy was very high and very low, respectively.

The series of mutations designed to either "activate autophagy in a hyper efficient way or switch it off" have been described in a paper published in the journal Nature Communications.

"Autophagy is significantly linked with neurodegenerative disorders, including Parkinson's disease, and cancer," corresponding author on the study Lipi Thukral, a computational biologist, senior principal scientist and associate professor at CSIR-IGIB, Academy of Scientific and Innovative Research , said.

Studies have shown autophagy to play a dual role in cancer it can suppress a tumour's growth by preventing an accumulation of damaged material, but can also promote survival of a cancer cell by helping it develop a resistance to anti-cancer agents, among other methods.

In neurodegenerative diseases, including Parkinson's and Alzheimer's diseases, autophagy is impaired, contributing towards a toxic clumping of protein aggregates within a cell, which can cause cell death.

"This is a study largely to say that autophagy, a cell's cleansing process, can be a very relevant therapeutic target. It can now be modulated, and anything which can be changed, you can study it in the disease condition. Because the moment you switch it off, you can now see what is happening in cancer or Parkinson's disease," Thukral told PTI.

"So, the study is a fundamental one, with the next step having a potential direct therapeutic implication. We have also put out international patents for these engineered proteins," she said.

Thukral proposed that an engineered LC3 protein could be potentially delivered within cells via lipid nanoparticles to see how enhancing or reducing the body's capability to perform autophagy changes the disease condition.

This is also a recent technology underlying mRNA vaccines, she said.

Messenger ribonucleic acid or mRNA vaccines, widely used against Covid-19, carry genetic instructions for a cell to create a harmless part of a pathogen, training the immune system to fight the real infection safely.

Thukral is currently working with collaborators in Germany and the UK to test out the programmable autophagy in cancer cells and Parkinson's disease.

Ravi Manjithaya, an autophagy researcher and professor and chair of the molecular biology and genetics unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bengaluru, described the study as a "tour de force" that combines computational analysis with rigorous experimental validation.

"It is almost like having a magic wand to clear the garbage in Bengaluru. If you understood where the bottleneck was and could directly target it, you can imagine how effectively the city could be made garbage-free," Manjithaya told PTI.

"Now, at the molecular level, if you had a way of bringing the autophagy machinery directly to the garbage and accelerating its clearance, you would be doing something truly remarkable," he explained.

Manjithaya, who has been studying autophagy for more than two decades, said that the paper explains how to make the clearance of garbage more efficient.

"It is therefore a tour de force study not one that relies solely on computational predictions, but one that takes the findings through the entire spectrum of structural analysis, biochemical validation and cellular experiments," he added.

According to Manjithaya, one of the most immediate areas where such an approach could have implications is neurodegeneration, particularly diseases in which the accumulation of misfolded proteins or damaged mitochondria the energy-producing organelles of cells is a central problem. These include Alzheimer's, Parkinson's and Huntington's diseases.

"With the advent of AI/ML, computational structural biology is increasingly accessible even to scientists who are not specialists in the field. This creates an exciting test bed for generating a large number of new hypotheses based on how we interrogate and interpret biological structures," he said.

Thukral said, "When biology data and compute infrastructure align so beautifully, then we can have really meaningful discoveries. That's what is happening in the current era. In a lot of ways, we are entering an era where it is predicted that we'll solve diseases at a greater pace."

She added that potential pharmaceutical partners could take up the work for future therapeutic applications. The innovation would hence be available for greater public good.

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