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Reversible conformational change of tau2 epitope on exposure to detergent in glial cytoplasmic inclusions of multiple system atrophy

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Abstract

Tau-like immunoreactivity (IR) on glial cytoplasmic inclusions (GCIs) of multiple system atrophy (MSA) was investigated with a panel of anti-tau antibodies and we found that tau2, one of the phosphorylation-independent antibodies, preferentially immunolabeled GCIs. Co-presence (0.03%) of polyethyleneglycol-p-isooctylphenyl ether (Triton X-100, TX) with tau2, however, abolished this IR on GCIs, but did not abolish tau2 IR on neurofibrillary tangles (NFTs). Tau2-immmunoreactive bands on immunoblot of brain homogenates from MSA brains were retrieved mainly in a TRIS-saline-soluble fraction, as reported in normal brains. This was in contrast to SDS-soluble fractions from brain with Down's syndrome, which contained tau2-immuoreactive bands of higher molecular weight. It indicates that the appearance of tau2 IR on GCIs is not related to hyperphosphorylation of tau. These tau2-immunoreactive bands, except those from bovine brain, were similarly abolished in the presence of TX (0.06%), and repeated washing after exposure to TX restored the tau2 IR on immunohistochemistry and on immunoblot. These findings can be explained if the modified tau2 epitope undergoes a reversible conformational change on exposure to TX, which is reversible after washing. Because the conformation centered at Ser101 of bovine tau is crucial for its affinity to tau2, the Ser-like conformation mimicked by its human counterpart Pro may represent pathological modification of tau shared by GCIs and NFTs. The relative resistance of tau2 epitope on NFTs on exposure to TX suggests that tau woven into NFTs confers additional stability to the pathological conformation of tau2 epitope. The conformation of the tau2 epitope in GCIs is not as stable as in NFTs, suggesting that tau proteins are not the principal constituents of the fibrillary structures of GCIs, even though they were immunodecorated with tau2. The difference in the susceptibility of the tau2 epitope to TX may distinguish its conformational states, which are variously represented according to disease conditions.

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Authors and Affiliations

  1. Department of Neurology and Psychiatry, Kanagawa Rehabilitation Center, 516 Nanasawa Atsugi-shi, 243-0121, Kanagawa-ken, Japan

    Katsuhiko Shibuya & Kiyoshi Iwabuchi

  2. Department of Neuropathology, Tokyo Metropolitan Institute for Neuroscience, 2-6 Musashi-dai, Fuchu, 183-8526, Tokyo, Japan

    Katsuhiko Shibuya, Toshiki Uchihara & Ayako Nakamura

  3. Department of Pathology, Kanagawa Rehabilitation Center, 516 Nanasawa Atsugi-shi, 243-0121, Kanagawa-ken, Japan

    Miyako Ishiyama, Keiko Yamaoka & Saburo Yagishita

  4. Department of Psychiatry, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, 236-0004, Yokohama, Japan

    Kenji Kosaka

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  1. Katsuhiko Shibuya
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Correspondence to Toshiki Uchihara.

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Shibuya, K., Uchihara, T., Nakamura, A. et al. Reversible conformational change of tau2 epitope on exposure to detergent in glial cytoplasmic inclusions of multiple system atrophy. Acta Neuropathol 105, 508–514 (2003). https://doi.org/10.1007/s00401-003-0675-4

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  • DOI: https://doi.org/10.1007/s00401-003-0675-4

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