Work done in the lab of Prof. Samir K Maji at the Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay
About author
Dr. Surabhi Mehra did her bachelor’s and Master’s in Biotechnology. She earned a gold medal in her Master’s and was determined to pursue a career in research. She then joined Prof. Samir K Maji’s lab at the Indian Institute of Technology Bombay (IITB) as a PhD scholar in 2014. She was involved in various projects to explore multidisciplinary aspects of disease amyloids. She used extensive biophysical tools and cell biology techniques to study protein aggregation pathway(s) and develop a structure-function relationship of intermediate aggregates. Presently, Dr. Mehra is working as a postdoctoral fellow at the Tanz Centre for Neurodegenerative disorders (Tanz CRND), University of Toronto, Canada. She believes in implementing her knowledge of amyloid biology in developing effective therapies against neurodegenerative disorders.
Interview
How would you explain your research outcomes to the non-scientific community?
Neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and related disorders, are becoming the major public health issues in the elderly population. The increased rate of these incurable neurodegenerative disorders has devastating impacts on individuals and their families.
Neurodegeneration starts from an abnormal accumulation of a protein in the brain, which interferes with its normal functions and impairs the patient’s ability to carry out daily activities. The condition worsens over time until it becomes full-blown dementia. More concerning is that these neurodegenerative disorders are variable and show differences in clinical and pathological representations. In prion diseases, such as Creutzfeldt–Jakob disease (CJD) and Kuru diseases, this variability has been linked to the presence of ‘strains’ of protein aggregates in the brain. These protein strains emerge due to structural variations in protein aggregates and induce differences in disease symptoms, incubation period, the severity of the disease, and pathology, similar to bacterial or viral strains. The proteins like α-synuclein (α-Syn), amyloid-β (Aβ), and tau are believed to exhibit prion-like strain behaviour and display polymorphism in their aggregates. As a result of amyloid polymorphism, it becomes challenging to identify the potential targets for developing drugs to reduce the progression of these diseases.
Our research primarily addresses how a single protein (like α-Syn) can exist in different forms under identical aggregating conditions. Upon cellular or environmental insults, α-Syn undergoes structural conversion from a disordered state to amyloid form. During that conversion process, it forms heterogeneous and metastable aggregation intermediates, which are usually difficult to track. We designed an in vitro model system where we could monitor and isolate these aggregation intermediates. We found that these aggregation intermediates can convert into structurally diverse and biologically active polymorphs of α-Syn protein. These polymorphs differentially internalise in neuronal and glial cells, seed their endogenous monomeric counterpart, and transfer from one cell to another, reminiscent of prions. Thus, our work offers a novel approach to studying complex aggregation pathways and provides insights into the origin of fibril polymorphism, which could be beneficial in the future for designing conformational-based drugs against PD and related disorders.
How do these findings contribute to your research area?
α-Syn aggregation is the main event in Parkinson’s disease and other synucleinopathies. Many researchers all over the globe are trying to target the key species involved in the aggregation of this protein to design a cocktail of drugs and antibodies recognizing epitopes of α-Syn. Our step-wise approach to isolate intermediate species formed over the course of α-Syn aggregation has helped resolve the complexity of the aggregation cascade. The study has unveiled how specific structural elements of the polymorphs are linked to the toxicity and prion-like spread of aggregates in cells. It has revealed that the relative abundance and nature of the aggregation intermediates could dictate the propagation of a particular polymorph.
“The study has unveiled how specific structural elements of the polymorphs are linked to the toxicity and prion-like spread of aggregates in cells.”
What was the exciting moment during your research?
Usually, whenever you get some mind-boggling results in research, you become exhilarated, and your curiosity to find more doubles up. There were a lot of exciting moments during my research. The exciting moment I had was every time while isolating the helical intermediates. It was the most tedious and challenging part of the study. Successfully isolating α-helix from the kinetics mixture used to be my ‘made my day’ moment. The second was visualising transfer of fluorophore-labelled aggregates of the protein from one cell to another and the generation of endogenous protein aggregates in cells under confocal microscopy.
What do you hope to do next?
There are still many open and unanswered questions in the field. For instance, what are the exact species responsible for the death of neurons? How is a single protein able to affect different parts of the brain in different proteopathies? How can we engineer the cells to get rid of the accumulated fibril load and halt the progression of the disease? How are the protein strains evolving in the brain? What are the potential molecular targets in the brain for developing novel therapeutic interventions against neurodegenerative disorders? The magnitude of these questions calls for innovative basic research aimed at determining the root cause of the disease.
I look forward to working on different aspects of neurodegeneration and exploring novel avenues to identify potential targets for developing therapies to cure neurodegenerative disorders.
Where do you seek scientific inspiration from?
Science is a treasure of unexplored facts, uncharted data, and unanswered questions. Being a scientist, the quest to discover novel things and address the unsolved mysteries of science itself has been an inspiration for me.
How do you intend to help Indian science improve?
India has a pool of great scientists and researchers. As a part of this community, I believe we should aim to collaborate and network within academia as well as industries all over the globe to maximise the use of available resources and scientific talent. We should support new research initiatives and instil practical knowledge in young minds to emphasise more on the fundamentals of science.
Reference
Surabhi Mehra, Sahil Ahlawat, Harish Kumar, Debalina Datta, Ambuja Navalkar, Nitu Singh, Komal Patel, Laxmikant Gadhe, Pradeep Kadu, Rakesh Kumar, Narendra N. Jha, Arunima Sakunthala, Ajay S. Sawner, Ranjith Padinhateeri, Jayant B. Udgaonkar, Vipin Agarwal, Samir K. Maji, α-Synuclein Aggregation Intermediates form Fibril Polymorphs with Distinct Prion-like Properties,
Journal of Molecular Biology, Volume 434, Issue 19, 2022, 167761,
https://doi.org/10.1016/j.jmb.2022.167761.
Copy Editor: Anjali Mahilkar
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