Figure 4.

Relationship of tau with axonal transport. (A) Differential expression of tau protein isoforms arise from translation of MAPT splice variants. The MAPT H1 haplotype is directly oriented, whereas the H2 haplotype is due to an inverted sequence of approximately 970 kb. Alternative splicing events at exons 2 and 3 generate tau protein with zero (0N), one (1N), or two (2N) N-terminal repeats. Tau protein with three (3R) or four (4R) tandem repeats is generated from alternative splicing at exon 10. H1 causes relatively increased expression of exon 10, and therefore 4R tau. H2 causes increased exon 3 expression, and therefore 2N tau. Figure adapted from Wade-Martins [60]. (B) Comparison of axonal transport in healthy and Parkinson's disease (PD) dopaminergic neurons. In healthy brain, an increasing tau gradient from proximal to distal helps to drive axonal transport mediated by transport proteins, particularly kinesin and dynein. In the PD brain, risk-associated MAPT variants increase 4R tau expression, which is more prone to aggregation. α-Synuclein impairs axonal transport. Autophagosomes must be cleared from the synapse to the soma to fuse with the lysosome for protein degradation, but this clearance is reduced as a result of axonal trafficking impairment.