Abstract
SummaryThe 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.
Highlights
Chromosome 17q21 represents an interesting genomic locus featuring an $1.3–1.6 Mb region of linkage disequilibrium (LD) encompassing the microtubule-associated protein tau (MAPT) gene, including genetic variants associated with several neurodegenerative disorders
Tauopathies show differing aggregation compositions of tau protein, with principally 4R tau aggregating in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia with Parkinsonism associated with chromosome 17 (FTDP-17) (Arai et al, 2001; Buee Scherrer et al, 1996); 3R tau proteins aggregating in Pick’s disease (Delacourte et al, 1996); and both 3R and 4R tau aggregating in Alzheimer’s disease (Sergeant et al, 1997; Williams, 2006)
Eight induced pluripotent stem cells (iPSCs) clones made from three H1/H2 individuals were selected for use in this study (Figure 1A, see Table S1)
Summary
Chromosome 17q21 represents an interesting genomic locus featuring an $1.3–1.6 Mb region of linkage disequilibrium (LD) encompassing the microtubule-associated protein tau (MAPT) gene, including genetic variants associated with several neurodegenerative disorders. Strong association of MAPT H1 haplotype variants has been shown with progressive supranuclear palsy (PSP) (Hoglinger et al, 2011), corticobasal degeneration (CBD) (Kouri et al, 2015), and Parkinson’s disease (PD) (Nalls et al, 2014). The gene expresses six transcripts through the alternative splicing of exons 2, 3, and 10 resulting in six major tau protein isoforms in the adult CNS (Andreadis et al, 1992; Goedert et al, 1989). Tau proteins have been shown to aggregate in those brain regions that degenerate in a number of diseases, collectively referred to as tauopathies. Despite having a strong genetic association with MAPT, PD does not typically give rise to tau tangle pathologies
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
