Abstract
Microtubules (MTs) play a fundamental role in many vital processes such as cell division and neuronal activity. They are key structural and functional elements in axons, supporting neurite differentiation and growth, as well as transporting motor proteins along the axons, which use MTs as support tracks. Tau is a stabilizing MT associated protein, whose functions are mainly regulated by phosphorylation. A disruption of the MT network, which might be caused by Tau loss of function, is observed in a group of related diseases called tauopathies, which includes Alzheimer’s disease (AD). Tau is found hyperphosphorylated in AD, which might account for its loss of MT stabilizing capacity. Since destabilization of MTs after dissociation of Tau could contribute to toxicity in neurodegenerative diseases, a molecular understanding of this interaction and its regulation is essential.
Highlights
Tau is a microtubule-associated protein (MAP; Weingarten et al, 1975; Witman et al, 1976) that is abundant in the axons of neurons where it stabilizes microtubule (MT) bundles (Binder et al, 1985; Black et al, 1996)
This model was initially built using distance measurements based on Förster Resonance Energy Transfer (FRET) detection between pairs of fluorophores attached to Tau (Jeganathan et al, 2006)
The first site is in agreement with models proposing that the residues 269–284 (R2)-R3 would encompass the interface between tubulin (Kadavath et al, 2015a; Kellogg et al, 2018)
Summary
Tau is a microtubule-associated protein (MAP; Weingarten et al, 1975; Witman et al, 1976) that is abundant in the axons of neurons where it stabilizes microtubule (MT) bundles (Binder et al, 1985; Black et al, 1996). Tau binding to MTs, as well as its propensity to aggregate, are affected by Tau mutations and by Tau PTMs, in particular, its hyper-phosphorylation (Alonso et al, 1994; LeBoeuf et al, 2008). These pathologically modified Tau molecules perturb MT function and axonal transport, contributing to neurodegeneration. Mislocalized Tau in neurons of Tau-overexpressing transgenic mouse brain and of human AD brain directly interacts with the nucleoporins of the nuclear pore complex This interaction disrupts the nuclear pore functions of nucleocytoplasmic transport and might contribute to Tau-related neurotoxicity (Eftekharzadeh et al, 2018). This emphasizes the need to understand the finer details of structural and functional aspects of Tau/MTs interaction
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