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Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies

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Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies International Journal of Molecular Sciences Review Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies M. Catarina Silva * and Stephen J. Haggarty Chemical Neurobiology Laboratory, Center for Genomic Medicine, Departments of Neurology & Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA; [email protected] * Correspondence: [email protected] Received: 28 October 2020; Accepted: 22 November 2020; Published: 25 November 2020 Abstract: Tauopathies are neurodegenerative diseases characterized by the pathological accumulation of microtubule-associated protein tau (MAPT) in the form of neurofibrillary tangles and paired helical filaments in neurons and glia, leading to brain cell death. These diseases include frontotemporal dementia (FTD) and Alzheimer’s disease (AD) and can be sporadic or inherited when caused by mutations in the MAPT gene. Despite an incredibly high socio-economic burden worldwide, there are still no effective disease-modifying therapies, and few tau-focused experimental drugs have reached clinical trials. One major hindrance for therapeutic development is the knowledge gap in molecular mechanisms of tau-mediated neuronal toxicity and death. For the promise of precision medicine for brain disorders to be fulfilled, it is necessary to integrate known genetic causes of disease, i.e., MAPT mutations, with an understanding of the dysregulated molecular pathways that constitute potential therapeutic targets. Here, the growing understanding of known and proposed mechanisms of disease etiology will be reviewed, together with promising experimental tau-directed therapeutics, such as recently developed tau degraders. Current challenges faced by the fields of tau research and drug discovery will also be addressed. Keywords: tau; aggregation; neurodegeneration; Alzheimer’s disease; frontotemporal dementia; pathogenicity; therapeutics; immunotherapy; tau degrader 1. MAPT and Tauopathy Spectrum Disorders Over a century after its first described case, Alzheimer’s disease (AD) is the most prevalent form of tauopathy and the most common cause of dementia (~60–80% of cases), and its frequency of incidence is rapidly increasing as the world’s population aged >65 continues to increase. Approximately 5.8 million Americans lived with AD in 2019, and this is predicted to double by 2050 [1,2], together with a financial burden predicted to increase from its current annual US $259 billion to more than $1 trillion by 2050. This trend is predicted to be global unless means of delaying, preventing, or treating AD are found [1,3]. The microtubule-associated protein tau (MAPT) is a neuronal protein that regulates microtubule stability and dynamics as well as axonal transport [4,5]. Tau binds to microtubules via repeat microtubule-binding domains in the C-terminus, and this process is regulated by phosphorylation of sites within and adjacent the binding region (Figure1a,b) [ 6]. The N-terminal projection region plays a role in signal transduction and membrane interactions (Figure1a) [ 6]. Other tau physiological functions include interaction with the plasma membrane and scaffold proteins, signal transduction, DNA/RNA protection, and regulation of synaptic function [7,8]. In the human central nervous system (CNS), six tau isoforms are expressed by alternative splicing of the MAPT 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 (Figure1a) [ 9]. This process is developmentally regulated and Int. J. Mol. Sci. 2020, 21, 8948; doi:10.3390/ijms21238948 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 8948 2 of 49 specific to each brain region based on physiological function [10,11]. Exons 2 and 3 are translated into the N1 and N2 domains, respectively, producing the 0N, 1N, and 2N tau isoforms of the N-terminal projection region (Figure1a). 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 in the C-terminal region (Figure1a). Inclusion of exon 10 leads to the expression of three tau isoforms with four microtubule-binding domains (4R-Tau), whereas exclusion of exon 10 leads to expression of three isoforms of 3R-Tau [10,12]. These four repeat domains (R1–R4, Figure1a) 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 maintained at 1:1 [10,11]. Despite its protein domains, tau’s 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 β-sheet-rich paired helical filaments (PHFs) that subsequently deposit in the form of neurofibrillary tangles (NFTs) (Figure1b) are implicated in a heterogeneous group of aging-related neurodegenerative disorders referred to as tauopathies, which include Alzheimer’s disease (AD), Pick’s disease (PiD), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP) (Table1)[ 15–29]. While many MAPT mutations increase tau’s 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 poorly understood [31–33]. Evidence indicates that native tau is highly soluble, contains several charged and hydrophilic residues, and shows little tendency for aggregation. Thus, for tau to become aggregation competent, it must undergo conformational and post-translational modifications (PTMs) within and near the hexapeptide motifs in the C-terminal repeat domain (Figure1b,c) [ 34,35], which also makes 4R-Tau more aggregation prone [36,37]. Little is known about the consequences of tau loss-of-function, but reduced binding of hyperphosphorylated tau to axonal microtubules may alter their structure and/or function, disrupting axonal transport, driving synaptic dysfunction and loss, and promoting neurotoxicity. Int. J. Mol. Sci. 2020, 21, 8948 3 of 49 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 49 FigureFigure 1. Human 1. Human microtubule microtubule associated associated protein protein Tau physiological Tau physiological function function and in disease.and in (disease.a) Alternative (a) splicingAlternative of the splicing MAPT of gene the leadsMAPT to gene developmentally leads to developmentally regulated regulated expression expression of six Tau of six isoforms, Tau containingisoforms, three containing (3R) or three four (3R) (4R) or microtubule four (4R) microtubule (MT)-binding (MT) domains-binding domains in the C-terminus, in the C-terminus, and zero, oneand or two zero, N-terminus one or two N domains.-terminus domains. (b) Simplified (b) Simplified representation representation of Tau of Tau function function as as a a regulator regulator of of microtubule stability and dynamics in human neurons. Tau binding is regulated by microtubule stability and dynamics in human neurons. Tau binding is regulated by phosphorylation phosphorylation via the concerted action of kinases and phosphatases. In disease Tau becomes via the concerted action of kinases and phosphatases. In disease Tau becomes hyperphosphorylated hyperphosphorylated and no longer binds microtubules, contributing to axonal dysfunction. and no longer binds microtubules, contributing to axonal dysfunction. Together with post-translational Together with post-translational modification, Tau misfolding drives oligomerization and modification, Tau misfolding drives oligomerization and aggregation into larger order insoluble aggregation into larger order insoluble fibrils such as NFTs and PHFs found in the somatodendritic fibrilsspace such and as processes NFTs and of PHFs CNS foundneurons. in ( thec) Tau somatodendritic undergoes extensive space post and-translational processes of modification CNS neurons. (c) Tau(PTMs), undergoes which extensiveare exacerbated post-translational in disease. Indicated modification in the (PTMs), 2N4R Tau which isoform are exacerbated are the locations in disease. of Indicatedhighest in PTM the 2N4R density, Tau including isoform arephosphor the locationsylation, ofacetylation, highest PTM O-GlcNAcylation density, including and ubiquitination. phosphorylation, acetylation,Also indicated O-GlcNAcylation are sites of phosphorylation and ubiquitination. prevalent Also indicatedin tauopathies are sites and ofkey phosphorylation regulatory kinases. prevalent in tauopathies and key regulatory kinases.
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