title: Differential interaction and aggregation of 3-repeat and 4-repeat tau isoforms with 14-3-3zeta protein.
abstract: Tau isoforms, 3-repeat (3R) and 4-repeat tau (4R), are differentially involved in neuronal development and in several tauopathies. 14-3-3 protein binds to tau and 14-3-3/tau association has been found both in the development and in tauopathies. To understand the role of 14-3-3 in the differential regulation of tau isoforms, we have performed studies on the interaction and aggregation of 3R-tau and 4R-tau, either phosphorylated or unphosphorylated, with 14-3-3zeta. We show by surface plasmon resonance studies that the interaction between unphosphorylated 3R-tau and 14-3-3zeta is approximately 3-folds higher than that between unphosphorylated 4R-tau and 14-3-3zeta. Phosphorylation of tau by protein kinase A (PKA) increases the affinity of both 3R- and 4R-tau for 14-3-3zeta to a similar level. An in vitro aggregation assay employing both transmission electron microscopy and fluorescence spectroscopy revealed the aggregation of unphosphorylated 4R-tau to be significantly higher than that of unphosphorylated 3R-tau following the induction of 14-3-3zeta. The filaments formed from 3R- and 4R-tau were almost similar in morphology. In contrast, the aggregation of both 3R- and 4R-tau was reduced to a similar low level after phosphorylation with PKA. Taken together, these results suggest that 14-3-3zeta exhibits a similar role for tau isoforms after PKA-phosphorylation, but a differential role for unphosphorylated tau. The significant aggregation of 4R-tau by 14-3-3zeta suggests that 14-3-3 may act as an inducer in the generation of 4R-tau-predominant neurofibrillary tangles in tauopathies.
authors.affiliation: Department of Psychiatry, Osaka University, Yamadaoka, Suita, Japan.
authors.forename: Golam
authors.initials: G
authors.lastname: Sadik
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Tanaka
authors.forename: Kiyoko
authors.initials: K
authors.lastname: Kato
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yanagi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kudo
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda