FIGURE 1.

Tau isoforms generated through tau gene expression, alternative RNA splicing, and protein translation. (A) Tau biosynthesis in the CNS. Tau is found on chromosome 17 arm 21. The tau gene contains 16 exons. Exons 1, 4, 5, 7, 13 (light gray) and 9, 11, 12 (light green) are all constitutively transcribed in the CNS (Martin et al., 2011). Exons 9, 11, and 12 encode the R1, R3, and R4 domains, respectively (Martin et al., 2011; Goedert et al., 2017). Exon 10 encodes the R2 domain. Exon -1 is part of the promotor region and is not translated. Exons 4A, 6, and 8 (orange) are mostly expressed in peripheral tissues. Exon 14 is a part of the 3’ untranslated region of the mRNA sequence and is not translated (Goedert et al., 1989; Andreadis, 2005). Tau isoforms are generated by alternate splicing of exons 2 and 3 (light and dark blue) and exon 10 (dark green). The six isoforms range from 352 to 441 amino acids and can be referred to by the clone name as well. Structurally, tau is subdivided into the N-terminal domain, the proline rich domain, microtubule-binding domain region, and the C-terminal domain. (B) R domain MTBR primary sequences. The primary amino acid sequences of the microtubule binding region (MTBR) shows that R1 (243–273), R2 (274–304), R3 (305–335), and R4 (336–367) are partially repeated sequences (Barbier et al., 2019). 275 VQIINK 280 and 306 VQIVYK 311 are two motifs within R2 and R3 that have strong MT interactions and are important for intermolecular β-sheet formation (Moreno-Castillo et al., 2020).