Much More Than a Cytoskeletal Protein: Physiological and Pathological Functions of the Non-microtubule Binding Region of Tau

Abstract

Tau protein (MAPT) is classified as a microtubule-associated protein (MAP) and is believed to regulate the axonal microtubule arrangement. It belongs to the tau/MAP2/MAP4 family of MAPs that have a similar microtubule binding region at their carboxy-terminal half. In tauopathies, such as Alzheimer's disease, tau is distributed more in the somatodendritic compartment, where it aggregates into filamentous structures, the formation of which correlates with cognitive impairments in patients. While microtubules are the dominant interaction partners of tau under physiological conditions, tau has many additional interaction partners that can contribute to its physiological and pathological role. In particular, the amino-terminal non-microtubule binding domain (N-terminal projection region, NTR) of tau interacts with many partners that are involved in membrane organization. The NTR contains intrinsically disordered regions (IDRs) that show a strong evolutionary increase in the disorder and may have been the basis for the development of new, tau-specific interactions. In this review we discuss the functional organization of the tau protein and the special features of the tau non-microtubule binding region also in the connection with the results of Tau KO models. We consider possible physiological and pathological functions of tau's non-microtubule interactions, which could indicate that interactions mediated by tau's NTR and regulated by far-reaching functional interactions of the PRR and the extreme C-terminus of tau contribute to the pathological processes.

Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies

“…Tau protein is enriched in axons where it binds microtubules through its MTBD and participates in their stabilization and regulation. Tau protein's "free" flanking N-terminal and C-terminal regions interact with various classes of proteins involved in the regulation of cytoskeleton [56,57] and motor proteins kinesins and dyneins [58,59]. Thus, tau participates in the regulation of intraneuronal transport and modulation of microtubule dynamics, which ensures flexible reorganization of cytoskeleton and synaptic transmission.…”

Tau: A Signaling Hub Protein

“…Such flexibility represents another characteristic of tau documented by extensive structural and biophysical studies (Mandelkow and Mandelkow, 2012 ; Sabbagh and Dickey, 2016 ; Stern et al, 2017 ). Indeed, intrinsically disordered proteins, including tau, are known for their unique structural plasticity, conformational adaptability, and binding promiscuity enabling their involvement in diverse signaling roles (Uversky, 2015 ; Brandt et al, 2020 ). Interestingly, there is a clear evolutionary increase in disorder within the amino-terminal region of tau that likely enabled the development of novel protein-protein interactions (Trushina et al, 2019 ).…”

Space-occupying brain lesions, trauma-related tau astrogliopathy, and ARTAG: a report of two cases and a literature review

“…ARTAG and severe (advanced-stage) CTE are astrocytopathies characterized by astrocytic tau inclusions. The normal functions of tau protein are debated [24][25][26] and the roles for tau proteins in glial cells are mostly unknown. In the adult human brain, six tau isoforms are generated by alternative splicing of the microtubule associated protein tau (MAPT) gene.…”