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From the Department of Ultrastructure and Histochemistry (Dr. Arima), Tokyo Institute of Psychiatry, Tokyo; the Departments of Laboratory Medicine (Drs. Arima and Kawai) and Neurology (Drs. Kawai and Sunohara), National Center Hospital for Mental, Nervous, and Muscular Disorders, and the Divisions of Demyelinating Disease and Aging (Drs. Kowalska, Takahashi, and Tabira), Degenerative Disease (Dr. Mukoyama), and Immunology (Dr. Watanabe), National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira; and the Department of Neuropathology and Neuroscience (Drs. Hasegawa and Iwatsubo), Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo, Japan.
Address correspondence and reprint requests to Dr. Kunimasa Arima, Department of Ultrastructure and Histochemistry, Tokyo Institute of Psychiatry, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, Japan; e-mail: arima{at}prit.go.jp
OBJECTIVE: To characterize the clinical diagnostic features, neuropathologic phenotype of tau deposition, and subunit structure of tau filaments in patients who had an asparagine-to-lysine substitution at codon 279 (the N279K missense mutation) of the gene for microtubule-associated tau protein.
BACKGROUND: The N279K mutation is a causative genetic defect for pallidopontonigral degeneration in an American kindred that presents with frontotemporal dementia (FTD) and parkinsonism.
METHODS: The authors analyzed retrospectively the clinical symptoms of two Japanese brothers who carry this mutation. Postmortem neuropathologic and electron microscopic studies, and Western blot analysis of insoluble tau were performed to correlate tau-mediated lesions with neurologic deficits.
RESULTS: Both patients exhibited impairment in recent memory, parkinsonism, and corticospinal disturbances in addition to FTD. Parkinsonism in one patient was responsive temporarily to L-dopa. There was intense tau deposition in the medial temporal cortices and upper and lower motor neurons with accompanying corticospinal tract degeneration. Two distinct tau isoforms with four microtubule-binding repeats, in hyperphosphorylated forms, were the primary constituents of insoluble tau, which aggregated to the filamentous component, termed "paired tubules," in neurons, oligodendrocytes, and astrocytes. The elemental filaments were hollow tubules measuring 11 to 12 nm in diameter, two of which adhered to each other along their longitudinal axes to form "paired tubules."
CONCLUSIONS: Early memory loss and pyramidal signs, which are atypical of FTD, can be presenting symptoms in this disorder. The authors demonstrated that the subunit structure of tau filaments is a pair of hollow tubules despite the prevailing twisted ribbon model.
Key words: Frontotemporal dementia—Mutation—Parkinsonism—Tau
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