Abstract
The H1 haplotype of the microtubule-associated protein tau (MAPT) gene is a common genetic risk factor for some neurodegenerative diseases such as progressive supranuclear palsy, corticobasal degeneration, and Parkinson’s disease. The molecular mechanism causing the increased risk for the named diseases, however, remains unclear. In this paper, we present a valuable tool of eight small molecule neural precursor cell lines (smNPC) homozygous for the MAPT haplotypes (four H1/H1 and four H2/H2 cell lines), which can be used to identify MAPT-dependent phenotypes. The employed differentiation protocol is fast due to overexpression of NEUROGENIN-2 and therefore suitable for high-throughput approaches. A basic characterization of all human cell lines was performed, and their TAU and α-SYNUCLEIN profiles were compared during a differentiation time of 30 days. We could identify higher levels of conformationally altered TAU in cell lines carrying the H2 haplotype. Additionally, we found increased expression levels of α-SYNUCLEIN in H1/H1 cells. With this resource, we aim to fill a gap in neurodegenerative disease modeling with induced pluripotent stem cells (iPSC) for sporadic tauopathies.
Highlights
A major class of neurodegenerative diseases are tauopathies which are characterized by intracellular inclusions of the microtubule-associated protein tau (MAPT) in neurons
The selected cell lines were further analyzed regarding their genotype for single nucleotide polymorphisms (SNPs) in the MAPT gene and in the SNCA gene coding for α-SYNUCLEIN
All iPS cell lines were converted into small molecule neural precursor cell lines (smNPC) via embryoid body formation and dual SMAD inhibition (Figures 1A,B)
Summary
A major class of neurodegenerative diseases are tauopathies which are characterized by intracellular inclusions of the microtubule-associated protein tau (MAPT) in neurons. Over 50 known mutations in the MAPT gene causing familial forms of frontotemporal lobar degeneration with TAU inclusions (FTLD-TAU; Ghetti et al, 2015) include missense mutations that alter the amino acid sequences of TAU and splice mutations which influence the alternative splicing of exon 10 (Goedert, 2005). Apart from these autosomal dominant mutations, there are several genetic risk factors that increase the risk for neurodegenerative diseases like tauopathies
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