A new study elucidates the molecular mechanisms that may explain how mutations of the tau gene give rise to frontotemporal dementia and parkinsonism (FTDP-17), an inherited disorder that is similar to Alzheimer's disease. In this week's issue of Science, Ming Hong and colleagues at the University of Pennsylvania describe how different FTDP-17 mutations impair specific properties of tau. Some mutations affected the alternative splicing that generates different isoforms of tau. Another dysfunction reduces tau's ability to bind microtubules and promote microtubule assembly. Analyses of the proteins from those patients' brains indicated that different mutations differentially altered distinct biochemical properties of the tau protein. "There's no doubt that tau tangles alone can lead to disease, while you cannot say that for the amyloid plaques," says John Q. Trojanowski, a professor of pathology and laboratory medicine and coauthor on the study. "These results suggest that sporadically formed tau tangles, similar to those found in hereditary FTDP-17, may be causal features in many neurodegenerative diseases, including Alzheimer's disease."—June Kinoshita
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- Hong M, Zhukareva V, Vogelsberg-Ragaglia V, Wszolek Z, Reed L, Miller BI, Geschwind DH, Bird TD, McKeel D, Goate A, Morris JC, Wilhelmsen KC, Schellenberg GD, Trojanowski JQ, Lee VM. Mutation-specific functional impairments in distinct tau isoforms of hereditary FTDP-17. Science. 1998 Dec 4;282(5395):1914-7. PubMed.