Brain Advance Access originally published online on March 26, 2004
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Brain, Vol. 127, No. 6, 1415-1426, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh147
Frontotemporal dementia with Pick-type histology associated with Q336R mutation in the tau gene
1 Department of Old Age Psychiatry, Institute of Psychiatry, 2 Reta Lila Weston Institute of Neurological Studies, University College London, 3 Department of Neuropathology, Institute of Neurology, Queen Square, London, 4 Departments of Pathology and Clinical Genetics, Aberdeen Royal Infirmary, Aberdeen, 5 Department of Psychological Services and Research, Dumfries and Galloway Health Board, Nithbank, Dumfries, 6 Greater Manchester Neurosciences Centre, University of Manchester, Hope Hospital, Salford, UK, 7 Department of Neuroscience, Mayo Clinic, Jacksonville, USA, 8 Department of Molecular Neurobiology, Tokyo Institute of Psychiatry and 9 Department of Psychogeriatrics, Tokyo Institute of Psychiatry, Tokyo, Japan
*These authors contributed equally to the study. Correspondence to: Professor D. Mann, Greater Manchester Neurosciences Centre, Humphrey Booth Building, Hope Hospital, Stott Lane, Salford M6 8HD, UK. E-mail: david.mann{at}man.ac.uk
In this report, we describe the clinical and neuropathological features of a case of familial frontotemporal dementia (FTD), with onset at 58 years of age and disease duration of 10 years, associated with a novel mutation, Q336R, in the tau gene (tau). In vitro studies concerning the properties of tau proteins bearing this mutation, with respect to microtubule assembly and tau filament aggregation, are reported. Clinically, the patient showed alterations in memory, language and executive functions and marked behavioural change consistent with FTD, although the extent of memory impairment was more than is characteristic of FTD. At autopsy, there was degeneration of the frontal and temporal lobes associated with the presence of hyperphosphorylated tau proteins in swollen (Pick) cells and intraneuronal inclusions (Pick bodies). By immunohistochemistry, the Pick bodies contained both 3-repeat and 4-repeat tau proteins although, because no fresh tissues were available for analysis, the exact isoform composition of the aggregated tau proteins could not be determined. Neurons within frontal cortex contained neurofibrillary tangle-like structures, comprising both straight and twisted tubules, or Pick bodies in which the filaments were short and randomly orientated. In vitro, and in common with other tau missense mutations, Q336R caused an increase in tau fibrillogenesis. However, in contrast to most other tau missense mutations, Q336R increased, not decreased, the ability of mutant tau to promote microtubule assembly. Nonetheless, this latter functional change may likewise be detrimental to neuronal function by inducing a compensatory phosphorylation that may yield increased intracellular hyperphosphorylated tau species that are also liable to fibrillize. We believe the mutation is indeed pathogenic and disease causing and not simply a coincidental rare and benign polymorphism. Since this mutation is segregating with the FTD clinical and neuropathological phenotype, it has not been found in unaffected individuals and it has novel functional properties in vitro which are likely to be detrimental to neuronal function in vivo.
Key Words: frontotemporal dementia; tau mutation; tau pathology; microtubule binding; fibrillogenesis
Abbreviations: FTD= frontotemporal dementia; FTDP-17 = frontotemporal dementia with parkinsonism linked to chromosome 17; NFT = neurofibrillary tangle; 3R = 3-repeat; 4R = 4-repeat
Received November 5, 2003. Revised January 15, 2004. Accepted January 29, 2004.
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