MAPT Genetic Variation and Neuronal Maturity Alter Isoform Expression Affecting Axonal Transport in iPSC-Derived Dopamine Neurons

The H1 haplotype of the microtubule-associated protein tau (MAPT) locus is genetically associated with neurodegenerative diseases, including Parkinson's disease (PD), and affects gene expression and splicing. However, the functional impact on neurons of such expression differences has yet to be fully elucidated. Here, we employ extended maturation phases during differentiation of induced pluripotent stem cells (iPSCs) into mature dopaminergic neuronal cultures to obtain cultures expressing all six adult tau protein isoforms. After 6 months of maturation, levels of exon 3+ and exon 10+ transcripts approach those of adult brain. Mature dopaminergic neuronal cultures display haplotype differences in expression, with H1 expressing 22% higher levels of MAPT transcripts than H2 and H2 expressing 2-fold greater exon 3+ transcripts than H1. Furthermore, knocking down adult tau protein variants alters axonal transport velocities in mature iPSC-derived dopaminergic neuronal cultures. This work links haplotype-specific MAPT expression with a biologically functional outcome relevant for PD. •iPSC-derived dopaminergic neurons express six adult tau isoforms after 6 months•Mature dopaminergic neuronal cultures show haplotype differences in MAPT expression•Tau isoform expression is affected by both common and rare genetic variation•Knockdown of tau variants alters axonal transport in dopaminergic neuronal cultures In this article, Caffrey, Wade-Martins, and colleagues show extended maturation of dopaminergic neuronal cultures gives expression of six adult tau isoforms displaying MAPT haplotype-specific differences in expression. Further, knocking down adult tau protein variants alters axonal transport velocities in mature iPSC-derived dopaminergic neuronal cultures, linking haplotype-specific MAPT expression with a biologically functional outcome relevant for PD.