期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：50
页码：E8187-E8196
DOI：10.1073/pnas.1616344113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe progressive nature of neurodegenerative diseases is due to the spread of prions, misfolded infectious proteins, in the brain. In tauopathies, the protein tau misfolds, causing several diseases, including Alzheimers disease (AD) and chronic traumatic encephalopathy (CTE). Here we created a panel of mammalian cell lines expressing a fragment of tau fused to yellow fluorescent protein. Each cell line selectively detects tau prions that are misfolded into self-propagating conformations; such cells permit identification of minute differences among tauopathies. For example, tau prions in AD and CTE are distinct from prions in other tauopathies such as Picks disease and progressive supranuclear palsy. These insights are likely to contribute to the development of future therapeutics. Tau prions are thought to aggregate in the central nervous system, resulting in neurodegeneration. Among the tauopathies, Alzheimers disease (AD) is the most common, whereas argyrophilic grain disease (AGD), corticobasal degeneration (CBD), chronic traumatic encephalopathy (CTE), Picks disease (PiD), and progressive supranuclear palsy (PSP) are less prevalent. Brain extracts from deceased individuals with PiD, a neurodegenerative disorder characterized by three-repeat (3R) tau prions, were used to infect HEK293T cells expressing 3R tau fused to yellow fluorescent protein (YFP). Extracts from AGD, CBD, and PSP patient samples, which contain four-repeat (4R) tau prions, were transmitted to HEK293 cells expressing 4R tau fused to YFP. These studies demonstrated that prion propagation in HEK cells requires isoform pairing between the infecting prion and the recipient substrate. Interestingly, tau aggregates in AD and CTE, containing both 3R and 4R isoforms, were unable to robustly infect either 3R- or 4R-expressing cells. However, AD and CTE prions were able to replicate in HEK293T cells expressing both 3R and 4R tau. Unexpectedly, increasing the level of 4R isoform expression alone supported the propagation of both AD and CTE prions. These results allowed us to determine the levels of tau prions in AD and CTE brain extracts.
