Abstract
Tau protein, a neuronal microtubule-associated protein, becomes hyperphosphorylated in several neurodegenerative diseases called tauopathies. Hyperphosphorylation of tau is correlated to its redistribution from the axon to the somato-dendritic compartment at early stages of tauopathies. Interestingly, tau hyperphosphorylation begins in different regions of the brain in each tauopathy. In some regions, both neurons and glial cells develop tau hyperphosphorylation. Tau hyperphosphorylation is also observed in physiological conditions such as hibernation and brain development. In the first section of present article, we will review the spatiotemporal and cellular distribution of hyperphosphorylated tau in the most frequent tauopathies. In the second section, we will compare the pattern of tau hyperphosphorylation in physiological and pathological conditions and discuss the sites that could play a pivotal role in the conversion of non-toxic to toxic forms of hyperphosphorylated tau. Furthermore, we will discuss the role of hyperphosphorylated tau in physiological and pathological conditions and the fact that tau hyperphosphorylation is reversible in physiological conditions but not in a pathological ones. In the third section, we will speculate how the differences and similarities between hyperphosphorylated tau in physiological and pathological conditions could impact the elaboration of therapies to prevent tau pathology. In the fourth section, the different therapeutic approaches using tau as a direct or indirect therapeutic target will be presented.
Highlights
Tau protein, a neuronal microtubule-associated protein, becomes hyperphosphorylated in several neurodegenerative diseases called tauopathies
We will compare the pattern of tau hyperphosphorylation in physiological and pathological conditions and discuss the sites that could play a pivotal role in the conversion of non-toxic to toxic forms of hyperphosphorylated tau
We will discuss the role of hyperphosphorylated tau in physiological and pathological conditions and the fact that tau hyperphosphorylation is reversible in physiological conditions but not in a pathological ones
Summary
Tau is mainly a neuronal microtubule-associated protein encoded by the MAPT gene on human chromosome 17q21 [1]. Tau undergoes several post-translational modifications in physiological conditions; phosphorylation being the predominant modification Most of these modifications impact tau function and contribute to the heterogeneity of tau forms found in developing and adult brain [7]. In neurodegenerative diseases called tauopathies, tau becomes hyperphosphorylated destabilizing its interaction with microtubules, accumulates and self-aggregates in insoluble filaments [7, 10]. This aggregation of tau is correlated to neurodegeneration [11, 12]. We will review the spatiotemporal pattern of the propagation of tau pathology and the cellular distribution of hyperphosphorylated tau in AD and the three most studied primary tauopathies: PSP, CBD, and PID.
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