Structures of α-Syn and Tau. (A) Model for the temporal sequence of synaptic events leading up to neuronal cell death in neurodegeneration. Synaptic dysfunction appears first, driving synaptic loss, and ultimately neurodegeneration. Synapses can be recovered during the early stage, offering a potential therapeutic window to counteract neuronal loss. Whether there is a causative connection in neurodegeneration remains to be shown. (B) Schematic overview of the α-Syn protein. The N-terminus (aa 1–60) contains amphipathic repeats. This sequence is followed by the NAC domain (aa 61–95). The negatively charged C-terminus (aa 96–140) contains the KFERQ-like VKKDQ sequence (aa 95–99, pink stripe). (C) Overview of the localization of Tau and α-Syn in neurons under native (left) and disease conditions (right). While α-Syn mainly resides in the presynapse, Tau is bound to microtubules in healthy neurons. However, in disease, Tau detaches from the microtubules and invades the presynaptic compartment. Eventually, both Tau and α-Syn are shown to accumulate resulting in dysfunctional presynapses. (D) The six neuronal Tau isoforms vary by the presence or absence of one/two inserts in the N-terminal domain (0N, 1N, 2N) and the presence of three or four repeat sequences in the MTBR (R2 absent or present, termed 3R or 4R Tau) that are generated by alternative splicing. Tau consists of four functional domains: an N-terminal projection domain Tau (aa 1–165), a PRR (aa 166–242), an MTBR (aa 243–367), and a C-terminal domain (aa 368–441). The MTBR encompasses the four partially repeated sequences: R1 (aa 243–273), R2 (aa 274–304), R3 (aa 305–335), and R4 (aa 336–367). Moreover, the protein contains two KFERQ-like motifs (336QVEVK340 and 347KDRVQ351) indicated in the scheme with pink stripes.