Tau: A Signaling Hub Protein

Abstract

Over four decades ago, in vitro experiments showed that tau protein interacts with and stabilizes microtubules in a phosphorylation-dependent manner. This observation fueled the widespread hypotheses that these properties extend to living neurons and that reduced stability of microtubules represents a major disease-driving event induced by pathological forms of tau in Alzheimer’s disease and other tauopathies. Accordingly, most research efforts to date have addressed this protein as a substrate, focusing on evaluating how specific mutations, phosphorylation, and other post-translational modifications impact its microtubule-binding and stabilizing properties. In contrast, fewer efforts were made to illuminate potential mechanisms linking physiological and disease-related forms of tau to the normal and pathological regulation of kinases and phosphatases. Here, we discuss published work indicating that, through interactions with various kinases and phosphatases, tau may normally act as a scaffolding protein to regulate phosphorylation-based signaling pathways. Expanding on this concept, we also review experimental evidence linking disease-related tau species to the misregulation of these pathways. Collectively, the available evidence supports the participation of tau in multiple cellular processes sustaining neuronal and glial function through various mechanisms involving the scaffolding and regulation of selected kinases and phosphatases at discrete subcellular compartments. The notion that the repertoire of tau functions includes a role as a signaling hub should widen our interpretation of experimental results and increase our understanding of tau biology in normal and disease conditions.

Neuronal and Glial Distribution of Tau Protein in the Adult Rat and Monkey

“…However, the functional repertoire of tau remains a matter of investigation and it appears to do much more than simply stabilize microtubules. In fact, evidence suggests tau is more likely involved in regulating microtubule dynamics (not stabilization), modulation of signaling pathways involved in axonal transport, and potentially additional roles including synaptic and nuclear functions, among others (Wang and Mandelkow, 2016;Combs et al, 2019;Mueller et al, 2021). The interest in better understanding tau function and dysfunction has steadily increased since the 1980's when it was identified as the primary constituent of the pathological inclusions in Alzheimer's disease (AD), known as neurofibrillary tangles (Brion et al, 1985;Delacourte and Défossez, 1986;Grundke-Iqbal et al, 1986a,b;Ihara et al, 1986;Kosik et al, 1986;Nukina and Ihara, 1986;Wolozin et al, 1986;Wood et al, 1986;Dickson et al, 1987).…”

Frontotemporal Lobar Dementia Mutant Tau Impairs Axonal Transport through a Protein Phosphatase 1γ-Dependent Mechanism

“…However, recent work identified functional roles of tau unrelated to regulation of microtubule dynamics. Notably, tau plays a role in signal transduction by regulating the localization and enzymatic activity of kinases and phosphatases involved in a diverse set of cellular processes ( (Lee et al, 1998;Liao et al, 1998;Ittner et al, 2010) reviewed in (Kanaan et al, 2013;Mueller et al, 2021)).…”

Tau peptide signals are seen in Parkinson subjects by Broderick Probe® sensors

“…Positron Emission Tomography in cerebrospinal fluid is new and hopeful. 5 Nuclear magnetic resonance (NMR) for flexible Tau forms and Cryo-EM for the most rigid forms or fluid immuno-diagnosis coupled to brain imaging research such as the BRODERICK PROBE ® bring promise. Video microscopy enables another useful tool in this highly active and necessary research arena, both clinical and pre-clinical.…”

“…However, it is the Broderick Laboratory who identifies herein, the LIVE electroactive image for Tau in the precise striatal basal neurons of the living subject as a metal complex phosphorylated, dynamic and presenting with Parkinsonian disease in this clinical paper. Mueller et al, 5 posit: "tau functions as a signaling hub, regulating a wide set of cellular processes through the modulation of selected kinases and phosphatases." Thus, the elusive nature of Tau is no longer elusive as Tau is showcased herein as a dynamic redox reaction occurring LIVE in the brain of the living Tau patient and animal via the phosphorylated BRODERICK PROBE ® .…”

“…It is noteworthy that the conventional role of Tau resided in the maintenance of microtubule stability in axons, an established thesis that is highly questioned in current times. [2][3][4][5] Tau peptides and proteins are abundant in the neurons of the central nervous system (CNS). It is generally known that Tau is less common elsewhere but are also expressed at very low levels in CNS astrocytes and oligodendrocytes.…”