Work done in the lab of Dr. Krishnananda Chattopadhyay at CSIR- Indian Institute of Chemical Biology, Kolkata
About author
Bidisha Das pursued her Bachelor’s in Zoology from Calcutta University and Master’s in Life Sciences from Jawaharlal Nehru University, New Delhi. Bidisha qualified CSIR NET JRF in Life Science (2016). She joined Protein Folding Dynamics lab, CSIR-IICB for her doctoral studies in 2018 under the supervision of Dr. Krishnananda Chattopadhyay. Her research is interdisciplinary and involves delineating the role of metal ion cofactors in the aggregation of SOD1, that is associated with the motor neuron disease, ALS. She has received DBT Builder fellowship during her Master’s and the Carl Storm Diversity fellowship to attend 2022 Protein Folding Dynamics GRC held in Ventura, CA, USA.
Interview
How would you explain your research outcomes to the non-scientific community?
Motor neuron diseases are a group progressive neurodegenerative disorders that selectively targets motor neuron activity. ALS is one such motor neuron disease characterized by the loss of motor neurons in the brain and spinal cord. This results in loss of control over voluntary muscles with time, ultimately leading to respiratory muscle failure and death. One of the important pathological hallmarks of ALS is the aggregation of human Cu/Zn superoxide dismutase1 (SOD1). SOD1 is a metalloenzyme that scavenges reactive oxygen species from the cell, having two metal cofactors, Cu and Zn. Till date, more than 170 mutations of this protein have been linked to familial ALS. Our group had previously established a correlation between the stability, aggregation, and disease severity for a subset of these mutants. In the present study, we hypothesized that SOD1 undergoes liquid-liquid phase separation (LLPS) since it has been reported to accumulate within stress granules. Stress granules are membraneless organelles, believed to originate via a process called LLPS. Our results have revealed that SOD1 indeed undergoes LLPS when Zn is removed from it by chelation or when it is unable to bind the protein due to disease mutation. We found that conformational disorder in the protein drives its LLPS and Zn coordination prevents LLPS by reducing disorderedness. Prolonged LLPS inducing conditions cause the protein to undergo liquid to solid transition culminating in aggregation. SOD1 LLPS is reversible by addition of Zn but its aggregation is an irreversible process. Furthermore, we have shown that the phase separated condensates of SOD1 induce higher cytotoxicity than its aggregates.
How do these findings contribute to your research area?
There is no cure for ALS as of now. Disease modifying drugs like Riluzole are only able to extend survival time in patients by 6-19 months. The results of this study uncover an intermediate state in SOD1 upstream of aggregation. A detailed understanding of how these condensates evolve into stress granules and inclusion bodies intracellularly may open possibilities for development of therapeutic drugs targeting these intermediates in near future.
“The results of this study uncover an intermediate state in SOD1 upstream of aggregation.”
What was the exciting moment during your research?
There were quite a few exciting moments while we were working on this project. I still remember the day when after a series of failed attempts, we were finally able to observe SOD1 condensates for the first time under the fluorescence microscope.
What do you hope to do next?
I plan to study the misfolding and aggregation of different SOD1 mutants in mammalian cells and understand the mechanistic pathways involved in the downstream events of SOD1 aggregation occurring in the cell using biophysics and cell biology.
Where do you seek scientific inspiration from?
The greatest source of my scientific inspiration comes from my mentor Dr. Krishnananda Chattopadhyay who keeps me motivated steadily with his optimistic attitude and pushes me to always do better. The vast expanse of unexplored questions in my field also fuels my scientific curiosity.
How do you intend to help Indian science improve?
I aspire to contribute to Indian science by continuing to ask more questions and improve my research quality without compromising on my scientific integrity.
Reference
Bidisha Das, Sumangal Roychowdhury, Priyesh Mohanty, Azamat Rizuan, Joy Chakraborty, Jeetain Mittal, Krishnananda Chattopadhyay. A Zn-dependent structural transition of SOD1 modulates its ability to undergo phase separation. The EMBO Journal (2022)e111185. https://www.embopress.org/doi/abs/10.15252/embj.2022111185
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