For years scientists have tried to understand how and why tau, well known to researchers for its implication in Alzheimer’s disease, changes from its normal form to a harmful misfolded form.
A recent article in Biospace describes tau filaments as being ten thousand times thinner than a human hair. The original study was published in the Journal of Cell Science.
There is wide acceptance that neurodegenerative diseases represent some of the most complicated and distressing forms of illness.
It is for this reason that the recent successful study of tau by researchers at the Zuckerman Institute of Columbia University and Mayo Clinic holds immense promise.
About the Study
The brain of a patient who has a neurodegenerative disease generally has entire sections that are eaten away. The sections are replaced by tangles and clumps of misfolded proteins. Tau is a typical example of this process.
The researchers used advanced technology to analyze patients’ brain tissues.
Their analysis revealed how tau protein modifications may affect the way tau misfolds in brain cells and how that can be linked to the development of neurodegenerative disease.
The researchers were able to show that post-translational modifications (PTMs) play a critical role in tauopathies which are neurodegenerative diseases associated with the buildup of tau.
Mapping Tau With Cryo-EM
The team used two techniques to map tau’s structure and identify additional PTMs that are attached to its surface.
Columbia’s Dr. Anthony Fitzpatrick who led the study was responsible for introducing the first technique called cryo-electron microscopy (cryo-EM) a Nobel Prize-winning technology.
The technique enables the visualization of individual tau filaments from the brain tissue of deceased humans. Cryo-EM has been indispensable as a technique for investigating even the smallest biological structures.
Cryo-EM enabled Dr. Fitzpatrick and his team to reconstruct tau filament structures. This gave the researchers new insight into their formation, growth and how they spread.
The Second Technology
Even cryo-EM has its limitations although it did provide detailed images of proteins. The technology does not give a full picture due to the fact that, unlike mass spectrometry, it cannot recognize the microscopic PTMs on tau’s surface.
Therefore the team, which now included Dr. Nicholas Seyfried at Emory University, paired cryo-EM with mass spectrometry in order to pinpoint the chemical composition of PTMs on tau’s surface.
In this second part of the study, patients with two types of tauopathies were studied. The two types were Alzheimer’s and corticobasal degeneration (CBD) which is a rare and aggressive tauopathy. CBD affects one in ten thousand people.
Dr. Fitzpatrick summarizes the study as suggesting that PTMs are markers on the surface of proteins and also influence tau’s behavior.
A Primary Tauopathy
CBD is considered to be a primary tauopathy because it is mostly associated with misfolded tau proteins. The researchers believe that studying CBD will help them to understand how tau turns toxic in brain cells.
This, in turn, will lead to knowledge about secondary tauopathies such as Alzheimer’s which is not only caused by tau but by many different factors.
It is interesting to note that no tauopathies are the same. Not only do they affect different segments in the brain, but they also affect different cell types causing dissimilar symptoms. For instance, Alzheimer’s affects memory because it occurs in the hippocampus.
And For the Future . . .
Dr. Fitzpatrick said their plans are to expand their work into other tauopathies. He hopes it will assist researchers in identifying new biomarkers and stop the disease before symptoms occur. He calls it the roadmap for therapeutics and diagnostics. He said that these insights into neurodegenerative diseases may prevent the disease from wreaking havoc in the brain.
