Today's cell: Nobel Prize technology to see how the protein fibers of "toxic" brain form

Tau protein is a kind of marker protein in many kinds of brain diseases, such as Alzheimer's disease (AD), frontotemporal dementia, Parkinson's disease, chronic traumatic encephalopathy and so on Therefore, many scientists are exploring how tau protein changes from normal functional form to the wrong form of toxic nerve In a new study published online today in the top academic journal Cell, scientists from the Zuckerman Institute of Columbia University and Mayo Clinic in the United States worked together to carry out a detailed structural analysis of tau protein fibers from patients' brain tissue using the advanced cryo-EM technology and mass spectrometry Their findings provide important insights for the diagnosis and treatment of neurodegenerative diseases such as AD Under normal circumstances, tau protein is very rich in nerve cells, which is related to the dynamic stability of microtubules, and is very important for maintaining healthy brain function In the brain of patients with neurodegenerative diseases, tau protein will gather into insoluble filaments in the form of misfolding, and eventually form neurofibrillary tangles, causing damage to brain tissue The toxic tau protein accumulates in different regions of the brain or affects different types of cells, leading to different symptoms In this study, scientists first purified tau protein fibers from diseased tissues of patients with cortical basal ganglia degeneration (CBD) CBD, like ad, is a neurodegenerative disease Compared with AD, it may be caused by a variety of factors The main cause of CBD is the abnormal tau protein "Studying primary tau diseases like CBD helps us to understand the toxicity of this protein to brain cells." Professor Leonard petrucelli of the Mayo Clinic, one of the co authors, said "The brain of neurodegenerative disease patients is easy to recognize: the affected brain tissue is eroded and replaced by tangles or plaques formed by misfolded proteins such as tau protein." Tamta arakhamia, the first author of this study However, because tau protein fiber is very thin, only 1 / 10000 of human hair, it is very difficult to see how tau protein fiber is formed and how it differs in different etiologies in traditional imaging methods However, there are new technologies to solve this problem The team led by Dr Anthony Fitzpatrick of Columbia University used cryo EM technology to image these fibers and reconstruct the structure of tau protein fibers This technology uses electron beam as light source, and after image processing, the three-dimensional structure of protein molecules can be obtained at the level of atomic resolution In 2017, the scientist who developed cryo EM Technology won the Nobel Prize in chemistry While using cryo EM technology to obtain the "snapshot" of tau protein, the research team also combined mass spectrometry analysis to identify the additional chemical components on the surface of tau protein, i.e post translation modification of protein, such as ubiquitination, acetylation, phosphorylation, etc The researchers observed that tau protein fibers from CBD patients not only undergo a large number of post-translational modifications, but also can be seen after comparing with the tau protein fiber structure of AD patients In patients with different etiologies, tau protein fiber structure is not the same, and the difference of post-translational modifications has an important impact on the fiber structure difference "These results show that post-translational modification can not only be used as a biomarker on protein surface, but also affect the behavior of tau protein in fact." Dr Fitzpatrick concluded "This will inspire the development of diagnostic tools and the design of drugs, for example, that can be targeted at specific post-translational modifications to slow down disease progression." Next, the research team plans to continue to expand the research on other tau protein diseases and develop new disease models to accurately understand the changes in patients' brains "Neurodegenerative diseases are a very complex and painful category of diseases, but we hope to develop a roadmap for successful diagnosis and treatment with our colleagues and collaborators," the study authors said We look forward to the new insights provided by scientists to benefit patients as soon as possible.