Nat. Rev. Neurol. doi: /nrneurol

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Nat. Rev. Neurol. doi:10.1038/nrneurol.2015.225 Figure 2 Tau mutations and alternative splicing of the MAPT pre-mRNA in FTD Figure 2 | Tau mutations and alternative splicing of the MAPT pre-mRNA in FTD. a | Schematic of full-length human tau, tau441, showing, in green, various missense mutations that have been found in inherited cases of frontotemporal dementia (FTD) and, in red, sites that can be phosphorylated, some or all of which render tau abnormally hyperphosphorylated in Alzheimer disease (AD) and other tauopathies. b | In addition to the missense mutations, several silent mutations have been found in FTDs. These silent mutations and some of the missense mutations affect the alternative splicing of MAPT pre-mRNA, giving rise to a change in the usual 1:1 3R:4R ratio. Both missense mutations and mutations that alter this ratio promote abnormal hyperphosphorylation of tau similar to that found in the absence of any mutations in AD. In the presence of compromised protein phosphatase 2A activity, as seen in AD, hyperphosphorylation could induce conformational changes similar to those induced by FTD-associated mutations in MAPT. 3R/4R, three/four microtubule-binding domain repeats. Iqbal, K. et al. (2015) Tau and neurodegenerative disease: the story so far Nat. Rev. Neurol. doi:10.1038/nrneurol.2015.225