New Delhi: At a time when scientists are predicting that the COVID-19 pandemic is likely to have a long-lasting impact on Parkinson's disease (PD) with the condition expected to reach over 14 million cases worldwide by 2040, Alpha-synuclein (ASyn) - an aggregation of a protein - is being pegged by a group of Indian physicists as a crucial player in determining the pathology of the disease.
The aggregation is found in abundance in what is called the substantia nigra portion in the mid-brain of patients suffering from Parkinson’s disease.
Parkinson’s disease is a common neurodegenerative disease that has no cure.
Many researchers from across the world are studying the mechanism of how the protein forms the aggregates, and how the aggregation results in the death of neuronal cells observed in Parkinson’s disease. They believe that once these mysteries are uncovered, it could help develop a drug for the disease, which is badly needed and has been long overdue.
Unfortunately, the aggregation of ASyn is not something that is easy to understand.
The endpoint of the aggregation is the formation of small slender fibres or `fibrils’, in which the protein has a structure type, what is called a cross beta fold. The fibrils are well-studied thanks to a dye, Thioflavin T, which binds to the cross-beta structure and emits fluorescence. Scientists have solved the three-dimensional structures of the fibrils and have also learnt how to develop drugs to target them. However, these drugs do not work in clinical trials.
In a bid to find a solution to this very problem, scientists from IIT (ISM) Dhanbad and CSIR-Indian Institute of Chemical Biology, Kolkata, teamed up.
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While the IIT (ISM) team is being led by Dr. Umakanta Tripathy, a physicist who studies nonlinear behaviour of biomaterials using Z-scan technique, a machine built by him, the CSIR-Indian Institute of Chemical Biology team is led by Dr. Krishnananda Chattopadhyay, a biophysicist who has been working to understand ASyn aggregation and its implications in Parkinson’s disease.
The team has found that the Z-scan method is the technique they have been looking for.
It could help in monitoring both the early and late stages of the aggregation of ASyn nicely. They found that the protein possesses linearity starting from its monomeric state to the fibrillar structure.
They have made three particularly interesting observations: first, the strength of non-linearity is relatively stronger in the case of fibrils when compared to other conformations of the protein, and second, each of the different conformers populated in the different stages of the aggregation landscape seems to have a specific non-linear property that could be targeted. The third and the most important result was a switch in the sign of nonlinearity when the late oligomers form at around 24 hours.
These late oligomers are supposed to be the most toxic species of ASyn and a method - which monitors these conveniently - can be really useful for both pharmaceutical and clinical research.
“Myself and my team at CSIR-IICB are exploring ways to use the Z-scan method to study ASyn aggregates ex vivo using a suitable animal Parkinson’s disease model, while Dr. Tripathy and his team planned to extend this method to other proteins and peptides to detect structures or conformations by systematic monitoring of their nonlinear values,” said Dr. Chattopadhyay.
