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Huntington's disease is a four-repeat tauopathy with tau nuclear rods


An imbalance of tau isoforms containing either three or four microtubule-binding repeats causes frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) in families with intronic mutations in the MAPT gene. Here we report equivalent imbalances at the mRNA and protein levels and increased total tau levels in the brains of subjects with Huntington's disease (HD) together with rod-like tau deposits along neuronal nuclei. These tau nuclear rods show an ordered filamentous ultrastructure and can be found filling the neuronal nuclear indentations previously reported in HD brains. Finally, alterations in serine/arginine-rich splicing factor-6 coincide with tau missplicing, and a role of tau in HD pathogenesis is evidenced by the attenuation of motor abnormalities of mutant HTT transgenic mice in tau knockout backgrounds.

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Figure 1: Increased 4R/3R tau isoform ratio and total tau protein content in HD brains, presence of TNRs in HD (and AD) brains and analysis of SRSF6 splicing factor in HD brains and in transfected human neuroblastoma SH-SY5Y cells.
Figure 2: SRSF6 alterations (presence in IBs and increased phosphorylation) in mutant HTT transgenic mice, increased 4R tau and total tau protein levels, presence of TNRs and attenuation of motor deficit by genetic reduction of tau.


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We thank P. Gómez-Ramos for helpful suggestions on electron microscopy experiments and A. Rábano and E. Gelpí for advice on human sample analysis. We also thank A. Tomico, M. Lucas and the team at the CBMSO Genomics Facility for their excellent technical assistance, as well as members of the Lucas lab for helpful advice and critical reading of the manuscript. P. Davies (Albert Einstein University) provided the PHF-1 antibody to phosphorylated tau; M. Novak (Slovak Academy of Sciences) and C.M. Wischik (University of Aberdeen) provided the 7.51 antibody to total tau; R. Kayed (University of Texas) provided the T22 antibody to oligomeric tau; S. Finkbeiner (Gladstone Institute) provided Htt constructs comprising the N-terminal fragment of Htt with 17 or 72 CAG repeats fused to the EGFP; and A.R. Krainer (Cold Spring Harbor Laboratory) provided SRSF6 expression vector. This work was supported by Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CiberNed–Instituto de Salud Carlos III) and by grants from Ministerio de Ciencia e Innovación (MICINN), Ministerio de Economía y Competitividad (MINECO), Comunidad Autónoma de Madrid, Fundación Ramón Areces and the Seventh Framework Programme of the European Commission (grant agreement 278486, project DEVELAGE). M.F.-N. was the recipient of a CSIC JAE-Pre research contract.

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J.J.L. directed the study. M.F.-N., J.R.C., M.S.-G., J.J.M.H. and I.F. designed and performed experiments. M.F.-N., J.R.C., J.J.M.H., A.J.M.R., I.F. and J.J.L. analyzed and interpreted the data. F.H. and J.A. made intellectual contributions to experimental design and discussion. J.J.L. wrote the manuscript.

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Correspondence to José J Lucas.

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The authors declare no competing financial interests.

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Fernández-Nogales, M., Cabrera, J., Santos-Galindo, M. et al. Huntington's disease is a four-repeat tauopathy with tau nuclear rods. Nat Med 20, 881–885 (2014).

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