Structural and functional differences between 3-repeat and 4-repeat tau isoforms - Implications for normal tau function and the onset of neurodegenerative disease

Tau, MAP2, and MAP4 are members of a microtubule-associated protein (MAP) f amily that are each expressed as "3-repeat" and "4-repeat" isoforms. These isoforms arise from tightly controlled tissue-specific and/or developmental ly regulated alternative splicing of a 31-amino acid long "inter-repeat:rep eat module," raising the possibility that different MAP isoforms may posses s some distinct functional capabilities. Consistent with this hypothesis, r egulatory mutations in the human tau gene that disrupt the normal balance b etween 3-repeat and 4-repeat tau isoform expression lead to a collection of neurodegenerative diseases known as FTDP-17 (fronto-temporal dementias and Parkinsonism Linked to chromosome 17), which are characterized by the form ation of pathological tau filaments and neuronal cell death. Unfortunately, very little is known regarding structural and functional differences betwe en the isoforms. In our previous analyses, we focused on 4-repeat tau struc ture and function. Here, we investigate 3-repeat tau, generating a series o f truncations, amino acid substitutions, and internal deletions and examini ng the functional consequences. 3-Repeat tau possesses a "core microtubule binding domain" composed of its first two repeats and the intervening inter -repeat. This observation is in marked contrast to the widely held notion t hat tau possesses multiple independent tubulin-binding sites aligned in seq uence along the length of the protein. In addition, we observed that the ca rboxyl-terminal sequences downstream of the repeat region make a strong but indirect contribution to microtubule binding activity in 5-repeat tan, whi ch is in contrast to the negligible effect of these same sequences in 4-rep eat tau. Taken together with previous work, these data suggest that 3-repea t and 4-repeat tau assume complex and distinct structures that are regulate d differentially, which in turn suggests that they may possess isoform-spec ific functional capabilities. The relevance of isoform-specific structure a nd function to normal tan action and the onset of neurodegenerative disease are discussed.