Scientists from Northwestern University and the University of California, Santa Barbara have developed a synthetic fragment of the tau protein, demonstrating prion-like characteristics. Known as the "mini prion," this synthetic tau fragment folds and aggregates into misfolded strands that transmit their abnormal shape to regular tau proteins.
These misfolded, prion-like proteins are crucial in the advancement of tauopathies, a set of neurodegenerative diseases, such as Alzheimer's disease, marked by the accumulation of misfolded tau proteins in the brain. Researchers believe that studying a synthetic version of human tau can advance diagnostic and therapeutic tools for these ailments.
The process revealed a critical role of water surrounding proteins in misfolding. A specific mutation changes the water dynamics around the tau protein, influencing its tendency to misfold.
“The scope of neurodegenerative diseases involving the protein tau is particularly broad,” said Songi Han from Northwestern University, the study's leader. Han's team focused on developing a small segment of tau protein, jR2R3, containing a mutation commonly present in these diseases, to function as a "seed" for templating misfolding. “We made a mini version that is easier to control,” Han added.
Cryogenic electron microscopy (cryo-EM) studies indicated that the P301L mutation facilitates misfolding akin to that observed in patients with neurodegeneration. "Water is a fluid molecule, but it still has structure," Han noted, highlighting the role of water in guiding the protein folding and aggregation process in diseased states.
The research team aims to further explore the properties and potential applications of these synthetic proteins in diagnostics and therapeutic developments for tau-related diseases. “Once a tau fibril is formed, it doesn’t go away,” Han said. “If we can figure out how to block this activity, then we could uncover new therapeutic agents.”
Their work, titled “Water-directed pinning is key to tau prion formation,” expects wide implications in the understanding and potential treatment of neurodegenerative disorders.