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First published online November 10, 2004
doi: 10.1242/10.1242/jcs.01558

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Tau phosphorylation in neuronal cell function and dysfunction

Department of Psychiatry, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA

View larger version (23K): [in a new window]   Fig. 1. Schematic diagram showing the organization of the six predominant isoforms of tau found in adult human brain. The number of amino acids (# aa) in each isoform is indicated at the right. The six isoforms are generated by splicing in or out exons 2 and 3 (E2 and E3) in the N-terminal region and exon 10 (E10) in the C-terminal region. The splicing in or out exon 10 results in a tau form with or without the second microtubule-binding repeat (R2), to yield isoforms with four or three microtubule-binding domains, respectively (Goedert et al., 1989). In fetal brain, only the shortest isoform of tau (352 amino acids) is present (Kosik et al., 1989). The proline-rich region is extensively phosphorylated in tau from Alzheimer's disease brain (reviewed by Johnson and Jenkins, 1999). The function of the N-terminal acidic region has not been clearly defined, although it might be involved in regulating the interaction of tau with the plasma membrane (Brandt et al., 1995).

View larger version (26K): [in a new window]   Fig. 2. In the development of tau pathology, tau phosphorylation events are probably sequential. In the early stages of pathology (`pretangle'), the predominant phosphorylation events are probably those that decrease the ability of tau to bind microtubules rather than those that increase the ability of tau to self-associate; this might be caused by an imbalance in the activity of specific protein kinases or phosphatases (Ptases). For example, pretangle neurons in Alzheimer's disease brain are labelled with antibodies that recognize phospho-Thr231 and phospho-Ser262 (Augustinack et al., 2002) and phosphorylation of both of these sites significantly decreases interactions of tau with microtubules (Biernat et al., 1993; Cho and Johnson, 2003). Subsequently, tau can be cleaved by caspase and/or phosphorylated at additional sites such as Ser422 (Ferrari et al., 2003; Haase et al., 2004) and Ser396/404 (Abraha et al., 2000), which increases the propensity of tau to oligomerize and eventually form filamentous aggregates. The exact role that tau oligomers and filaments play in the cell dysfunction/death process has not yet been clearly defined.

View larger version (31K): [in a new window]   Fig. 3. Tau phosphorylation plays both physiological and pathological roles in the cell. When the phosphorylation state of tau is appropriately coordinated, it plays a role in regulating neurite outgrowth (Biernat and Mandelkow, 1999; Biernat et al., 2002), axonal transport (Spittaels et al., 2000; Tatebayashi et al., 2004) and microtubule stability and dynamics (Cho and Johnson, 2004). However, in pathological conditions in which there is an imbalance in the phosphorylation/dephosphorylation of tau, aberrant tau phosphorylation can cause tau filament formation (Abraha et al., 2000), disrupt microtubule-based processes owing to decreased microtubule binding (Lu and Wood, 1993) and perhaps even increase cell death (Fath et al., 2002).