A new scientific model enables the study of fundamental interactions underlying neurodegenerative disease. This looks at the causative agent of such disease – prions. In particular, misfolded tau proteins are the hallmark of Alzheimer’s disease and frontotemporal dementia
Prions are a type of protein that transmit their abnormally folded shape onto other proteins. To facilitate the study of these biological fragments, the researchers designed a synthetic fragment of the tau protein that exhibits prion-like behaviour.
Scientists at Northwestern University and University of California, Santa Barbara combined resources to create the first synthetic fragment of tau protein that acts like a prion. The “mini prion” folds and stacks into strands (or fibrils) of misfolded tau proteins, which then transmit their abnormally folded shape to other normal tau proteins.
Misfolded, prion-like proteins drive the progression of tauopathies (resulting in neurodegenerative diseases) characterized by the abnormal accumulation of misfolded tau protein in the brain.
By studying a minimal synthetic version of the full-length human tau, scientists can better recreate the fibril structure containing misfolded tau proteins. This potentially could lead to targeted tools for diagnosis and therapy that are much needed for neurodegenerative diseases.
Creating self-propagating tau fragments that can recreate the fibril structure and misfolding that is unique to each tauopathy disease is seen by the scientists as a key step forward in their ability to understand and model these complex diseases.
While developing the synthetic protein, the scientists also uncovered new insights into the role of water around the protein surface that guides the misfolding process. A mutation commonly used to model tau-related diseases subtly changes the dynamic structure of water in the environment immediately surrounding the tau protein, the researchers found. This altered water structure influences the protein’s ability to adopt its abnormal shape.
Instead of recreating the entire length of the protein, which is long and unwieldy, the researchers aimed to pinpoint the shortest piece of tau that could still adopt a misfolded shape and form disease-like fibrils.
Using cryogenic electron microscopy (cryo-EM), the researchers solved the structure of the fibrils from samples of brain tissue. Although pinpointing the structure was a significant breakthrough, brain samples can only be obtained after a patient dies. Despite dramatic progress and intense interest in this area, final diagnosis of tau-related neurodegenerative diseases is only possible after death.
The research team is currently focused on further characterizing the properties of the synthetic, prion-like proteins. Eventually, the scientists plan to explore potential applications, including the development of new diagnostic and therapeutic approaches for tau-related diseases.
The research appears in the journal Proceedings of that National Academy of Sciences. The study is titled “Water-directed pinning is key to tau prion formation.”
