Assembly of two distinct dimers and higher-order oligomers from full-length tau

Naruhiko Sahara, Sumihiro Maeda, Miyuki Murayama, Takehiro Suzuki, Naoshi Dohmae, Shu Hui Yen, Akihiko Takashima

研究成果: Article査読

130 被引用数 (Scopus)

抄録

Abnormal accumulation of tau as filamentous structures is a neuropathological hallmark of neurodegenerative diseases referred to as tauopathies. Little is known about the role of native cysteine residues in tau assembly because their substitution with other amino acids has no effect on tau filament morphology. To understand the process involved in tau oligomerization, we analysed both heparin-induced assembly of different forms of recombinant human tau and assembly of tau from COS-7 cells transiently expressing different human tau constructs. Here, we demonstrated that tau assembly involves two distinct dimers (cysteine-dependent and cysteine-independent) that differ in resistance to reduction. During assembly, an increase of cysteine-dependent tau oligomer was observed prior to detection of increased thioflavin T fluorescence signals. The latter event was accompanied by an increase of cysteine-independent dimer. Fewer higher-order oligomers and aggregates were assembled from four-repeat tau containing two amino-terminus inserts that have either the C291A/C322A mutation (cysless-4R2N) or a hexapeptide deletion at residues 306-311 (ΔPHF6-4R2N) compared with those assembled from wild-type tau. Assembly of distinct types of dimers was also observed in lysates from COS-7 cells expressing wild-type 4R2N and brain extracts from mice expressing P301L mutant tau. In contrast, COS-7 cells expressing cysless- or ΔPHF6-4R2N tau contained very little cysteine-dependent dimer. Together, the results indicate that intermolecular disulfide crosslinking along with PHF6 hexapeptide facilitates tau oligomerization and that this event is accompanied by cysteine-independent intermolecular bridging of microtubule-binding domain, leading to assembly of higher-order oligomers. The levels of these dimers may be used to gauge the potential for tau assembly.

本文言語English
ページ(範囲)3020-3029
ページ数10
ジャーナルEuropean Journal of Neuroscience
25
10
DOI
出版ステータスPublished - 2007 5 1
外部発表はい

ASJC Scopus subject areas

  • 神経科学(全般)

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