Alzheimer's disease (AD) is the most common neurodegenerative disorder and is, on a histopathological level, characterized by the presence of extracellular amyloid plaques composed of the protein ...fragment Aβ, and intracellular neurofibrillary tangles, which contain the microtubule‐associated protein tau in a hyperphosphorylated state. In AD defects in microtubule (MT) assembly and organization have also been reported; however, it is unclear whether MT abnormalities have a causal and early role in the disease process or represent a common end point downstream of the neurodegenerative cascade. Recent evidence indicates that microtubule‐stabilizing drugs prevent axonopathy in animal models of tauopathies and reverse Aβ‐induced loss of synaptic connectivity in an ex vivo model of amyloidosis. This could suggest that MT dysfunction connects some of the degenerative events and provides a useful target to simultaneously prevent several neurodegenerative processes in AD. Here, we describe how changes in the structure and dynamics of MTs are involved in the different aspects of the neurodegenerative triad of AD. We discuss evidence that MTs are affected both by tau‐dependent and tau‐independent mechanisms but appear to be regulated in a distinct way in different neuronal compartments. We argue that modulation of MT dynamics could be of potential benefit but needs to be precisely controlled in a cell and compartment‐specific manner to avoid harmful side effects.
This article is part of the series “Beyond Amyloid”.
Microtubule abnormalities are a common feature in several neurodegenerative diseases. Here, we describe how changes in microtubule dynamics are involved in the different aspects of the neurodegenerative triad of Alzheimer's disease. We discuss evidence that microtubule dynamics is (mis)regulated in a distinct manner in different neuronal compartments. Modulation of microtubule dynamics could be of potential benefit, but needs to be precisely controlled in a cell and compartment‐specific manner to avoid harmful side effects.
This article is part of the series “Beyond Amyloid”.
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.
Stress granules (SGs) are cytosolic, nonmembranous RNA-protein complexes. In vitro experiments suggested that they are formed by liquid-liquid phase separation; however, their properties in mammalian ...cells remain unclear. We analyzed the distribution and dynamics of two paradigmatic RNA-binding proteins (RBPs), Ras GTPase-activating protein SH3-domain-binding protein (G3BP1) and insulin-like growth factor II mRNA-binding protein 1 (IMP1), with single-molecule resolution in living neuronal cells. Both RBPs exhibited different exchange kinetics between SGs. Within SGs, single-molecule localization microscopy revealed distributed hotspots of immobilized G3BP1 and IMP1 that reflect the presence of relatively immobile nanometer-sized nanocores. We demonstrate alternating binding in nanocores and anomalous diffusion in the liquid phase with similar characteristics for both RBPs. Reduction of low-complexity regions in G3BP1 resulted in less detectable mobile molecules in the liquid phase without change in binding in nanocores. The data provide direct support for liquid droplet behavior of SGs in living cells and reveal transient binding of RBPs in nanocores. Our study uncovers a surprising disconnect between SG partitioning and internal diffusion and interactions of RBPs.
The microtubule skeleton plays an essential role in nerve cells as the most importantstructural determinant of morphology and as a highway for axonal transport processes. Many ...neurodegenerativediseases are characterized by changes in the structure and organization of microtubulesand microtubule-regulating proteins such as the microtubule-associated protein tau, which exhibitscharacteristic changes in a whole class of diseases collectively referred to as tauopathies. Changes inthe dynamics of microtubules appear to occur early under neurodegenerative conditions and are alsolikely to contribute to age-related dysfunction of neurons. Thus, modulating microtubule dynamicsand correcting impaired microtubule stability can be a useful neuroprotective strategy to counteractthe disruption of the microtubule system in disease and aging. In this article, we review current microtubule-directed approaches for the treatment of neurodegenerative diseases with microtubules asa drug target, tau as a drug target, and post-translational modifications as potential modifiers of themicrotubule system. We discuss limitations of the approaches that can be traced back to the ratherunspecific mechanism of action, which causes undesirable side effects in non-neuronal cell types orwhich are due to the disruption of non-microtubule-related interactions. We also develop somethoughts on how the specificity of the approaches can be improved and what further targets could beused for modulating substances.
Tau is a neuronal microtubule-associated protein that is involved in the regulation of axonal microtubule assembly. However, as a protein with intrinsically disordered regions (IDRs), tau also ...interacts with many other partners in addition to microtubules. Phosphorylation at selected sites modulates tau’s various intracellular interactions and regulates the properties of IDRs. In Alzheimer’s disease and other tauopathies, tau exhibits pathologically increased phosphorylation (hyperphosphorylation) at selected sites and aggregates into neurofibrillary tangles. By bioinformatics means, we tested the hypothesis that the sequence of tau has changed during the vertebrate evolution in a way that novel interactions developed and also the phosphorylation pattern was affected, which made tau prone for the development of tauopathies. We report that distinct regions of tau show functional specialization in their molecular interactions. We found that tau’s amino-terminal region, which is involved in biological processes related to “membrane organization” and “regulation of apoptosis”, exhibited a strong evolutionary increase in protein disorder providing the basis for the development of novel interactions. We observed that the predicted phosphorylation sites have changed during evolution in a region-specific manner, and in some cases the overall number of phosphorylation sites increased owing to formation of clusters of phosphorylatable residues. In contrast, disease-specific hyperphosphorylated sites remained highly conserved. The data indicate that novel, non-microtubule related tau interactions developed during evolution and suggest that the biological processes, which are mediated by these interactions, are of pathological relevance. Furthermore, the data indicate that predicted phosphorylation sites in some regions of tau, including a cluster of phosphorylatable residues in the alternatively spliced exon 2, have changed during evolution. In view of the “antagonistic pleiotropy hypothesis” it may be worth to take disease-associated phosphosites with low evolutionary conservation as relevant biomarkers into consideration.
Tau is a microtubule-associated neuronal protein, whose primary role was long thought to regulate axonal microtubule assembly. Tau is subject to many posttranslational modifications and can aggregate ...into neurofibrillary tangles, which are considered to be a hallmark of several neurodegenerative diseases collectively called “tauopathies”. The most common tauopathy is Alzheimer's disease, where tau pathology correlates with sites of neurodegeneration. Tau belongs to the class of intrinsically disordered proteins, which are known to interact with many partners and are considered to be involved in various signaling, regulation and recognition processes. Thus more recent evidence indicates that tau functionally interacts with many proteins and different cellular structures, which may have an important physiological role and may be involved in neurodegenerative processes. Furthermore, tau can be released from neurons and exert functional effects on other cells. This review article weighs the evidence that tau has subtle but important systemic effects on neuronal network function by maintaining physiological neuronal transmission and synaptic plasticity, which are possibly independent from tau's microtubule modulating activities. Implications for tau-based therapeutic approaches are discussed.
•Tau protein is a promiscuous binder involved in signaling, regulation and recognition processes.•Tau is involved in neurodegenerative events triggered by various insults.•Tau has systemic effects on neuronal network function.•Side-effects by reducing tau levels need to be considered in tau-based therapies.
Alzheimer’s disease (AD) is characterised by a progressive loss of cognitive functions. Histopathologically, AD is defined by the presence of extracellular amyloid plaques containing Aβ and ...intracellular neurofibrillary tangles composed of hyperphosphorylated tau proteins. According to the now well-accepted amyloid cascade hypothesis is the Aβ pathology the primary driving force of AD pathogenesis, which then induces changes in tau protein leading to a neurodegenerative cascade during the progression of disease. Since many earlier drug trials aiming at preventing Aβ pathology failed to demonstrate efficacy, tau and microtubules have come into focus as prominent downstream targets. The article aims to develop the current concept of the involvement of tau in the neurodegenerative triad of synaptic loss, cell death and dendritic simplification. The function of tau as a microtubule-associated protein and versatile interaction partner will then be introduced and the rationale and progress of current tau-directed therapy will be discussed in the biological context.
Tauopathies such as Alzheimer's disease are characterized by aggregation and increased phosphorylation of the microtubule-associated protein tau. Tau's pathological changes are closely linked to ...neurodegeneration, making tau a prime candidate for intervention. We developed an approach to monitor pathological changes of aggregation-prone human tau in living neurons. We identified 2-phenyloxazole (PHOX) derivatives as putative polypharmacological small molecules that interact with tau and modulate tau kinases. We found that PHOX15 inhibits tau aggregation, restores tau's physiological microtubule interaction, and reduces tau phosphorylation at disease-relevant sites. Molecular dynamics simulations highlight cryptic channel-like pockets crossing tau protofilaments and suggest that PHOX15 binding reduces the protofilament's ability to adopt a PHF-like conformation by modifying a key glycine triad. Our data demonstrate that live-cell imaging of a tauopathy model enables screening of compounds that modulate tau-microtubule interaction and allows identification of a promising polypharmacological drug candidate that simultaneously inhibits tau aggregation and reduces tau phosphorylation.
Abstract The microtubule-associated tau proteins become functionally and structurally altered in Alzheimer's disease (AD). To analyze tau modification and its role in a non-vertebrate animal model, ...we produced transgenic Caenorhabditis elegans strains with a panneuronal expression of human tau and a pseudohyperphosphorylated (PHP) tau construct that mimics AD-relevant tau modification. We show that human tau in C. elegans becomes highly phosphorylated and exhibits conformational changes similar to PHP tau and human PHF tau. Both, wt tau and PHP tau induced a progressive age-dependent development of a phenotype of uncoordinated locomotion (unc) in the absence of neuronal degeneration. However, only PHP tau induced a defective pattern of motor neuron development as indicated by the presence of gaps in the dorsal cord, commissures on the wrong side and local broadening of axons. The data indicate that C. elegans is capable of highly phosphorylating human tau to an AD-like state whereas only stable disease-like tau modification induce developmental defects suggesting a specific interference of pathologic tau with intracellular mechanisms of axonal outgrowth and pathfinding.
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