6131 Tau interaction with microtubules in vivo

Neuronal microtubules (MTs) are essential for neurite extension, axonal guidance, and communication between the cell body and neuronal processes. Dynamic properties of individual MTs and the architecture of the MT array are regulated by MT-associated proteins (MAPs). One member of the MAP family, tau, has received particular attention since hyperphosphorylation of tau has been linked to the formation of abnormal filaments characteristic of Alzheimer's and other neurodegenerative diseases ('tauopathies') (Garcia and Cleveland, 2001; Lee et al., 2001). A large body of experimental evidence indicates that tau promotes MT stability and induces MT bundling in vitro (Drechsel et al., 1992; Kanai et al., 1992). Expression of tau in non-neuronal cells is sufficient to induce formation of neurite-like processes that contain arrays of parallel MTs (Baas et al., 1991; Knops et al., 1991; Lee and Rook, 1992), while lowering the level of tau expression in neuronal cells inhibits axonal growth (Caceres and Kosik, 1990). Although mice deficient in tau are essentially normal (Harada et al., 1994), knockout of both tau and MAP1B leads to serious neuronal defects (Takei et al., 2000), suggesting functional redundancy between these (and, perhaps other) MAPs. Interestingly, in humans, mutations in tau linked to some neurodegenerative diseases reduce the ability of tau to promote MT assembly (D'Souza et al., 1999; Hasegawa et al., 1999). Collectively, these data predict that tau-induced stabilization of the MT cytoskeleton is essential for proper development of nerve processes. Tau decoration of MTs appears to be uniform (Murphy and Borisy, 1975; Sloboda and Rosenbaum, 1979), and its binding to MTs is non-cooperative (Biernat et al., 1992). Electron microscopy studies suggest that tau binds to the outer surface of MTs and stabilizes tubulin-tubulin interactions along protofilaments (Al-Bassam et al., 2002). Binding of tau to MTs is phosphorylation-dependent and is regulated by several protein kinases (Drewes et al., 1998). Different isoforms of tau include three or four MT-binding repeats which are highly conserved between different species and different members of the MAP family (Goedert et al., 1996; Heidary and Fortini, 2001). 3R-tau and 4R-tau are developmentally regulated, and imbalances in their expression have been linked to neurodegenerative diseases (Hutton et al., 1998; Spillantini et al., 1998), suggesting a distinct function for each isoform. Further, even though both 3R-and 4R-tau induce neurite outgrowth in transfected cells, the onset of this outgrowth in 4R-tau-expressing cells is significantly more rapid (Yu et al., 2002). Immunocytochemical evidence indicates that tau …