(b) Simplified representation of Tau function as a regulator of microtubule stability and dynamics in human neurons

(b) Simplified representation of Tau function as a regulator of microtubule stability and dynamics in human neurons. recently developed tau degraders. Current difficulties confronted by the fields of tau research and drug discovery will also be resolved. exons 2, 3, and 10, of which the longest isoform 2N4R tau (441 amino acids) contains two N-terminal inserts and four repeat domains in the C-terminus region (Physique 1a) [9]. This process is usually developmentally regulated and specific to each Rabbit Polyclonal to PDCD4 (phospho-Ser457) brain region based on physiological function [10,11]. Exons 2 and 3 are translated into the N1 and N2 domains, respectively, generating the 0N, 1N, and 2N tau isoforms of the N-terminal projection region (Physique 1a). In the human adult brain, the 2N isoform is the least expressed while the 1N isoform is the most abundant [10]. Exon 10 encodes the second microtubule-binding repeat domain name in the C-terminal region (Physique 1a). Inclusion of exon 10 prospects to the expression of three tau isoforms with four microtubule-binding domains (4R-Tau), whereas exclusion of exon 10 prospects to expression of three isoforms of 3R-Tau [10,12]. These four repeat domains (R1CR4, Physique 1a) are essential for tau ability to regulate stability of microtubules and support axonal transport. For this reason, relative 3R/4R expression is also developmentally regulated. During the fetal stage, 3R-Tau (0N3R) is the main isoform present, allowing for dynamic axonal properties conducive to synaptogenesis and formation of neural pathways, followed by postnatal expression of all isoforms. In the adult brain, 4R-Tau binds more tightly to microtubules and the overall 3R/4R ratio is usually managed at 1:1 [10,11]. Despite its protein domains, taus native state defies the traditional structure-function paradigm by lacking a well-defined three-dimensional structure, being classified as an intrinsically disordered protein. This is a characteristic of proteins that require rapid conformational changes and structural plasticity but is also a characteristic of proteins with high propensity for misfolding that play a role in the pathogenesis of neurodegenerative diseases [13,14]. Tau misfolding and aggregation into highly ordered -sheet-rich paired helical filaments (PHFs) that subsequently deposit in the form of neurofibrillary tangles (NFTs) (Physique 1b) are implicated in a heterogeneous group of aging-related neurodegenerative disorders referred to as tauopathies, which include Alzheimers disease (AD), Picks disease (PiD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP) (Table 1) [15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]. While many mutations increase taus propensity for aggregation and toxicity, and are the cause of dominantly inherited tauopathies [30], the majority of tauopathies are sporadic with variable clinical and pathological presentations [15]. Tauopathies are mainly considered gain-of-function proteinopathies but, despite increasing understanding of tau physiology and role in disease, the mechanisms of tau aggregation with disruption of molecular pathways leading to neuronal death are still PRT062607 HCL poorly comprehended [31,32,33]. Evidence indicates that native tau is usually highly soluble, contains several charged and hydrophilic residues, and shows little tendency for aggregation. Thus, for tau to become aggregation qualified, it must undergo conformational and post-translational modifications (PTMs) within and near the hexapeptide motifs in the C-terminal repeat domain (Physique 1b,c) [34,35], which also makes 4R-Tau more aggregation prone [36,37]. Little is known about the consequences of tau PRT062607 HCL loss-of-function, but reduced binding of hyperphosphorylated tau to axonal microtubules may alter their structure and/or function, disrupting axonal PRT062607 HCL transport, driving synaptic dysfunction and loss, and promoting neurotoxicity. Open in a separate window Physique 1 Human microtubule associated protein Tau physiological function and in disease. (a) Option splicing of the MAPT gene prospects to developmentally regulated expression of six Tau isoforms, made up of three (3R) or four (4R) microtubule (MT)-binding domains in the C-terminus, and zero, one or two N-terminus domains. (b) Simplified representation of Tau function as a regulator of microtubule stability and dynamics in human neurons. Tau binding is usually regulated by phosphorylation via the concerted action of kinases and phosphatases. In disease Tau becomes hyperphosphorylated and no longer binds microtubules, contributing to axonal dysfunction. Together with post-translational modification, Tau misfolding drives oligomerization and aggregation into larger order insoluble fibrils such as NFTs and PHFs found in the somatodendritic space and processes of CNS neurons. (c) Tau undergoes considerable post-translational modification (PTMs), which are exacerbated in disease. Indicated in the 2N4R Tau isoform are the locations of highest PTM density, including phosphorylation, acetylation, O-GlcNAcylation and ubiquitination. Also indicated are sites of phosphorylation prevalent in tauopathies and key regulatory kinases. Table 1 Summary and important PRT062607 HCL features of main and secondary.