Study on involvement of of tau-binding factors in neurodegeneration

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Neurofibrillary tangles are neuropathological hallmarks of Alzheimer disease (AD) and other tauopathies including frontotemporal dementia (FTD) and corticobasal degeneration, and abnormally hyperphosphorylated tau protein is the major protein component of NFT. After finding of tau gene on chromosome 17 as a causative gene for familial FTD (FTDP-17), tau is thought to be essentially important for understanding of neurodegenerative processes in dementia. In brain of tauopathies tau is hyperphosphorylated and ubiquitinated, and self-assembles and forms filaments or aggregates, however the mechanisms of the involvement of tau in neurodegeneration are unclear.To understand the mechanisms of self-assembly of tau, we investigated the effects of phosphorylation of tau on the process self-assembly induced by 14-3-3. Phosphorylation of tau by protein kinase A (PKA) or protein kinase B (PKB), not glycogen synthase kinase-3, enhanced the binding of tau with 14-3-3, however PKA- or PKB-phosphorylation abolished the self-assembly of tau protein. And we investigated the effects of FTDP-17 mutations of tau on the process self-assembly induced by 14-3-3. The mutant tau (P301L, V337M and R406W) had higher affinity with 14-3-3 than wild type tau, and P301L tau induced the highest self-assembly level than others in the presence of 14-3-3. Our results suggest that phosphorylation and mutations of tau might play an important role in self-assembly of tau.