Tauopathies refer to a diverse set of sporadic and familial neurodegenerative disorders including Alzheimer’s disease (AD), and frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). All of these diseases have the formation of filamentous inclusions in both neurons and glia, which are composed primarily of hyperphosphorylated tau protein. The severity of the diseases appears to correlate with the extent of filamentous tau deposition. Understanding the mechanism under which tau fibrillizes has important implications for clarifying the pathogenesis of tauopathies.
Casein kinas 1 (CK1) family is serine/theronine specific protein kinases and they are highly associated with AD brain-derived tau filaments and granulovacuolar bodies, which are one of the hallmarks of AD and appear primarily within the hippocampus. At least six CK1 isoforms (CK1-α, γ1, γ2, γ3, δ, ε) are known to exist in human central nervous system. Real time RT-PCR was used to quantify the relative mRNA expression levels of CK1 isoforms in AD and non-AD control cases. Our data showed that of CK1-δ had 13-fold increase and CK1-γ2 had 4-fold increase in AD cases compared to control case. The rest of CK1 isoforms (CK1-α, γ1, γ3, ε) showed no statistical difference between AD and control groups. In conclusion, increased CK1-δ and CK1-γ2 mRNA levels in postmortem AD hippocampus indicate that CK1-δand CK1-γ2 might be candidate kinases involving in the hyperphosphorylation of tau in AD.
Recent genetic analysis has established a clear cause and effect relationship between tau gene intronic mutations and the autosomal dominant dementia in FTDP-17. These intronic mutations produce normal tau protein, but the 4R/3R isoform ratio is elevated. Since tau assembles via a nucleation dependent mechanism, using quantitative electron microscopy, the nucleation kinetics for 3R and 4R tau isoforms were assessed through the collection of critical concentrations and time courses. Our results show that 4R tau isoforms require much lower critical concentrations and possess higher nucleation efficiency than 3R tau isoforms. The dominant performance in fibrillization of 4R isoforms over 3R isoforms is accredited to the relative efficiency of exons 2, 3 and 10 in promoting tau monomer aggregation. Quantitative analysis demonstrates that exon 10 is a much stronger driving force to filament formation than exons 2, and 3.
In summary, hyperphosphorylation of tau by CK1 isoforms and increased exon 10 splice-in contribute to the aggregation of tau. Thus, CK1 isoforms and 4R tau isoforms may be valuable therapeutic targets for AD and other tauopatheis.