Protein aggregation is a phenomenon which results due to inadequacy of the cellular machinery to deal with misfolded or non-native proteins. It has been found to be associated with a number of human pathological disorders including neurodegenerative diseases such as Alzheimer’s, Parkinson’s, Huntington’s, and Prion diseases. Aggregation of the neuronal protein Tau results in the formation of fibrillar, rod-like structures (known as amyloid fibrils) in the brain, a phenomenon that has been implicated in a number of neurodegenerative diseases (tauopathies), including Alzheimer’s disease, frontotemporal dementia, progressive supranuclear palsy, Pick disease, primary age related tauopathy, and corticobasal degeneration. According to the World Health Organization, more than 47 million people worldwide are affected by dementia, with Alzheimer’s disease being the most common and widespread among them (60-70%). In this study, we were able to identify the conditions wherein intracellular Tau aggregates were found to be disassembled or disaggregated. Moreover, we were able to pinpoint the cellular machinery responsible for the disaggregation process. This study provides an opportunity to design therapeutic strategies for neurodegeneration affecting the disaggregation machinery for improved aggregate clearance.
Inside cells, protein misfolding is an unfavorable event that can result in the loss of biological activity or the formation of soluble and insoluble aggregates, the latter being associated with toxic effects underlying a number of human pathological disorders. Cells have mechanisms in place to prevent these aggregates from forming, either by preventing protein misfolding with molecular chaperones or by degrading misfolded proteins via proteolytic machineries. However, cellular machinery very frequently cannot take care of misfolded proteins, leading to their aggregation and accumulation in cells and tissues. Such protein aggregation has been implicated in a number of human pathological disorders including neurodegenerative diseases. Aggregation of the protein Tau has been implicated in Alzheimer’s disease, frontotemporal dementia and other pathologies referred to as tauopathies. Despite major research efforts world-wide, the mechanism of Tau aggregation and its pathogenesis giving rise to disease is not yet understood. Therapeutics to cure these tauopathies, including Alzheimer’s disease, are urgently needed. In our study, we were able to identify the conditions wherein intracellular Tau aggregates were found to be disassembled or disaggregated. Moreover, we were able to pinpoint the cellular machinery responsible for the disaggregation process.
