When proteins are made in a cell, they start out as strings of amino acids, which have to be folded into the correct, three-dimensional shape so they will function properly. Misfolded proteins can cause serious problems; they are a factor in tauopathies, which are neurodegenerative disorders like Alzheimer's disease, in which patients have misfolded tau protein tangles in the brain. Scientists have now created a synthetic protein fragment that behaves like a misfolded protein, which is also known as a prion. This mini-prion is a portion of tau, and it not only builds up, it spreads its abnormal shape to other, normal tau proteins. This synthetic tau fragment can now be used to learn more about prions, prion diseases, and neurodegenerative disorders.
In this work, the researchers showed how water molecules near a protein surface can influence misfolding. A mutation that is related to tauopathies has a subtle effect on water's dynamic structure in the area next to tau. The modified water structure impacts protein folding, altering a protein's ability to fold into its usual shape. The finding have been reported in the Proceedings of the National Academy of Sciences (PNAS).
"Creating self-propagating tau fragments that can recreate the fibril structure and misfolding that is unique to each tauopathy disease is a crucial step forward in our ability to understand and model these complex diseases," said senior study author Songi Han, a Professor at Northwestern University, among other appointments.
When normal tau proteins are exposed to aberrant tau fibrils, the normal protein adopts the wrong shape; a chain reaction is triggered that creates more and more misfolded proteins and aggregates. This is a phenomenon similar to what is seen in prions, which can spread from one person to another. But this prion-like behavior is not contagious (between people) in the case of tau.
Neurodegenerative diseases are not typically diagnosed by looking for tau tangles. Instead, doctors have to assess patients and analyze symptoms like memory problems.
"The bottleneck is the reliable generation of tau fibrils that recreate the critical and unique disease hallmarks to serve as targets for developing diagnostic strategies," Han explained.
Now that this synthetic prion model is available, the researches want to learn more about prion-like proteins and find ways to use them. For example, they may be applicable in the creation of diagnostic assays or treatments for tauopathies.
"Once a tau fibril is formed, it doesn't go away," Han said. "It will grab naïve tau and fold it into the same shape. It can keep doing this forever and ever. If we can figure out how to block this activity, then we could uncover new therapeutic agents."
Sources: Northwestern University, Proceedings of the National Academy of Sciences (PNAS)
