Tau Phosphorylation

Tau, a microtubule-associated protein (MAP), is well known within the context of Alzheimer’s disease (AD) as a main component of intraneuronal neurofibrillary tangles, which are a hallmark of AD and many other neurodegenerative diseases known as tauopathies. In the central nervous system (CNS), tau is a main MAP that normally binds to axonal microtubules to stabilize their quaternary structure during the dynamic process of microtubule assembly. Tau-mediated stabilization enables routine cargo transport along the microtubule highway that - in the context of long axonal projections - is critical for neuronal health and function. This stabilizing function is highly dependent on the generally flexible tertiary structure of tau, which is maintained through phosphorylation of specific sites throughout the protein in both the projection and microtubule binding domains. In the context of AD, tau kinase/phosphatase activity shifts, generating an altered and increased phosphorylation pattern throughout the protein that modifies its tertiary structure. As a result, tau’s capacity for microtubule stabilization is impaired, leading to increased microtubule catastrophe and faulty cargo trafficking. Importantly, pathological hyperphosphorylation of tau increases its susceptibility to aggregate into paired helical filaments, which form into large intracellular neurofibrillary tangles (NFTs), a noted hallmark of AD that is visible in diseased tissue. Microtubule destabilization and NFTs both contribute to the neurotoxicity and neurodegeneration associated with AD and tauopathies.

Selected Reviews:

• Barbier, P., Zejneli, O., Martinho, M., Lasorsa, A., Belle, V., Smet-Nocca, C., Tsvetkov, P. O., Devred, F., & Landrieu, I. (2019). Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects. Frontiers in Aging Neuroscience 11.
• Combs, B., Mueller, R. L., Morfini, G., Brady, S. T., & Kanaan, N. M. (2019). Tau and Axonal Transport Misregulation in Tauopathies. Advances in Experimental Medicine and Biology 1184, 81–95.
• Iqbal, K., Liu, F., Gong, C.-X., & Grundke-Iqbal, I. (2010). Tau in Alzheimer Disease and Related Tauopathies. Current Alzheimer Research 7(8), 656–664.
• Venkatramani, A., & Panda, D. (2019). Regulation of neuronal microtubule dynamics by tau: Implications for tauopathies. International Journal of Biological Macromolecules 133, 473–483.