Is the early stage of aggregation important in understanding neurodegenerative diseases?

	Although majority of the neurodegenerative diseases do not have any cure available, protein aggregation and deposition has been found to be a common phenotype. The heterogeneity of aggregation process and the presence of large number of triggering mechanisms results in the difficulty to devise therapeutic strategies against these toxic inclusions formation. Our laboratory has been investigating these triggers, which contribute to the alteration of folding pathways leading to the early and unexplored stages of aggregation. The conformational heterogeneity of the early intermediates and their transient nature are some of the reasons why traditional techniques do not typically work for the early stage detection. We have been using sensitive biophysical methods to directly detect and characterize the early intermediates and oligomers in vitro and inside live cells using Parkinson’s diseases (PD) and ALS as our models. We are also using cryo-EM to investigate the structural insights into the early intermediates, which are believed to the primary inducer of cellular toxicity. Using a combination of biophysics, biochemistry and microscopy, we are developing protein early intermediates vs toxicity maps to determine the structural insights responsible for the neuronal toxicity.