Tauopathies: Deciphering Disease Mechanisms to Develop Effective Therapies

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.

An approach to gene-based testing accounting for dependence of tests among nearby genes

“…Another locus of interest is a 1.5 Mb region of chromosome 17, namely 17q21 (Figure 5C). This region of the genome is well known in human genetics because it comprises a 1.5 Mb inversion polymorphism [30, 31] and the inversion alleles, actually haplotypes, have been associated with a wide variety of neurodegenerative disorders, including Progressive Supranuclear Palsy [32], corticobasal degeneration [33], frontotemporal dementia [34], and other tauopathies [35]. In this locus, altered MAPT is well known to affect risk for late-life neurodegenerative disorders.…”

Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

“…Interestingly, different tau isoforms are associated with different forms of neurodegeneration, defining a subset of pathologies termed tauopathies. Hence, in Pick's Disease only 3R tau is found, while in corticobasal degeneration and in progressive supranuclear palsy only 4R tau isoforms are present in degenerative brains [157,163]. In other tauopathies both forms could be found, although with different stoichiometry, as in the case of the behavioral variant of frontotemporal dementia (with 3R isoform overrepresented compared to the 4R), primary progressive aphasia and primary age-related tauopathy.…”

“…Furthermore, tau could be acetylated in some of the same residues targeted by ubiquitination. Thus, a model has been proposed [163] in which acetylation competes with ubiquitination, in turn avoiding the proteasomal system and favoring tau accumulation. Phosphorylation of tau is the most abundant PTM both in physiological and pathological contexts, with more than 80 phosphorylatable residues identified to date [176].…”

“…Experiments conducted with hexanediol and by manipulating salt concentrations indicated that, similar to acetylation, phosphorylation of tau increases its propensity to form hydrophobic-driven LLPS and, conversely, inhibits electrostatic-driven LLPS [179]. Hyperphosphorylated tau has been observed as the major form of tau present in pathological aggregates [157,158,163,165,176]. Whereas some phospho-sites, such as Ser262, Ser356, and Ser396 [163,180], are found at basal levels and are likely to be key regulatory elements, others are exclusively detected in disease (e.g., Ser422, Ser396/Ser404 and Ser208 [163]).…”

Deciphering the links between psychological stress, depression, and neurocognitive decline in patients with Down syndrome

“…Hyperphosphorylation of intracellular Tau proteins was later recognized to be a major step in AD, as it leads to dysregulation of the neural cytoskeleton, cytologically characterized by neurofibrillary tangles (NFTs) ( Silva and Haggarty, 2020 ). In AD, such NFTs are first observed in the hippocampus and entorhinal cortex, causing local cerebral atrophy, before wider cerebral extension ( Congdon and Sigurdsson, 2018 ).…”