GSK-3 and Tau: A Key Duet in Alzheimer's Disease.

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine kinase with a plethora of substrates. As a modulator of several cellular processes, GSK-3 has a central position in cell metabolism and signaling, with important roles both in physiological and pathological conditions. GSK-3 has been associated with a number of human disorders, such as neurodegenerative diseases including Alzheimer's disease (AD).

Discovery of autism/intellectual disability somatic mutations in Alzheimer's brains: mutated ADNP cytoskeletal impairments and repair as a case study.

With Alzheimer's disease (AD) exhibiting reduced ability of neural stem cell renewal, we hypothesized that de novo mutations controlling embryonic development, in the form of brain somatic mutations instigate the disease. A leading gene presenting heterozygous dominant de novo autism-intellectual disabilities (ID) causing mutations is activity-dependent neuroprotective protein (ADNP), with intact ADNP protecting against AD-tauopathy. We discovered a genomic autism ADNP mutation (c.

Single-cell analysis of cytoskeleton dynamics: From isoelectric focusing to live cell imaging and RNA-seq.

Focusing on microtubule heterogeneity and brain specificity allowed for initial discoveries of multiple tubulin isotypes four decades ago. Methods evolved from using radioactive labelling and single cell cultures to monoclonal antibodies recognizing discrete forms of tubulin in single neurons. With the advantage of molecular cloning and fluorescent protein tagging, essential components for microtubule dynamics/stability and function were identified, including activity-dependent neuroprotective protein, ADNP and its peptide snippet, NAP (drug candidate, davunetide/CP201).

Distinct Functions for Mammalian CLASP1 and -2 During Neurite and Axon Elongation.

Mammalian cytoplasmic linker associated protein 1 and -2 (CLASP1 and -2) are microtubule (MT) plus-end tracking proteins that selectively stabilize MTs at the edge of cells and that promote MT nucleation and growth at the Golgi, thereby sustaining cell polarity. analysis has shown that CLASPs are MT growth promoting factors. To date, a single CLASP1 isoform (called CLASP1α) has been described, whereas three CLASP2 isoforms are known (CLASP2α, -β, and -γ).

Role of tau N-terminal motif in the secretion of human tau by End Binding proteins.

For unknown reasons, humans appear to be particular susceptible to developing tau pathology leading to neurodegeneration. Transgenic mice are still undoubtedly the most popular and extensively used animal models for studying Alzheimer's disease and other tauopathies. While these murine models generally overexpress human tau in the mouse brain or specific brain regions, there are differences between endogenous mouse tau and human tau protein.

Atypical, non-standard functions of the microtubule associated Tau protein.

Since the discovery of the microtubule-associated protein Tau (MAPT) over 40 years ago, most studies have focused on Tau's role in microtubule stability and regulation, as well as on the neuropathological consequences of Tau hyperphosphorylation and aggregation in Alzheimer's disease (AD) brains. In recent years, however, research efforts identified new interaction partners and different sub-cellular localizations for Tau suggesting additional roles beyond its standard function as microtubule regulating protein. Moreover, despite the increasing research focus on AD over the last decades, Tau was only recently considered as a promising therapeutic target for the treatment and prevention of AD as well as for neurological pathologies beyond AD e.

ADNP/NAP dramatically increase microtubule end-binding protein-Tau interaction: a novel avenue for protection against tauopathy.

Activity-dependent neuroprotective protein (ADNP), vital for brain formation and cognitive function, is mutated in autism and linked to neurodegenerative/psychiatric diseases. An eight-amino-acid peptide snippet of ADNP, NAP (NAPVSIPQ), identified as a smallest active fragment, includes the SxIP microtubule (MT) end-binding protein (EB) association motif, and enhances ADNP-EB3 interaction. Depletion of EB1 or EB3 abolishes NAP protection against zinc intoxication.

Tau Structures.

Tau is a microtubule-associated protein that plays an important role in axonal stabilization, neuronal development, and neuronal polarity. In this review, we focus on the primary, secondary, tertiary, and quaternary tau structures. We describe the structure of tau from its specific residues until its conformation in dimers, oligomers, and larger polymers in physiological and pathological situations.

Tau antagonizes end-binding protein tracking at microtubule ends through a phosphorylation-dependent mechanism.

Proper regulation of microtubule dynamics is essential for cell functions and involves various microtubule-associated proteins (MAPs). Among them, end-binding proteins (EBs) accumulate at microtubule plus ends, whereas structural MAPs bind along the microtubule lattice. Recent data indicate that the structural MAP tau modulates EB subcellular localization in neurons.

Intracellular and extracellular microtubule associated protein tau as a therapeutic target in Alzheimer disease and other tauopathies.

Introduction: Microtubule associated protein tau, a protein mainly expressed in neurons, plays an important role in several diseases related to dementia, named tauopathies. Alzheimer disease is the most relevant tauopathy. The role of tau protein in dementia is now a topic under discussion, and is the focus of this review.

Tau regulates the localization and function of End-binding proteins 1 and 3 in developing neuronal cells.

The axonal microtubule-associated protein tau is a well-known regulator of microtubule stability in neurons. However, the putative interplay between tau and End-binding proteins 1 and 3 (EB1/3), the core microtubule plus-end tracking proteins, has not been elucidated yet. Here, we show that a cross-talk between tau and EB1/3 exists in developing neuronal cells.

Crosstalk between axonal classical microtubule-associated proteins and end binding proteins during axon extension: possible implications in neurodegeneration.

During neuronal development, spherical neuroblasts differentiate into mature neurons through the extension of a long axon and several shorter dendrites. Morphological changes that underlie neuronal differentiation are mostly driven by the microtubular cytoskeleton. Regulation of microtubule dynamics and stability during axon and dendrite extension relies on the action of different families of microtubular proteins, such as classical microtubule-associated proteins (MAPs) and microtubule plus-end tracking proteins (+TIPs).

Regulation of EB1/3 proteins by classical MAPs in neurons.

Microtubules (MTs) are key cytoskeletal elements in developing and mature neurons. MT reorganization underlies the morphological changes that occur during neuronal development. Furthermore, MTs contribute to the maintenance of neuronal architecture, enable intracellular transport and act as scaffolds for signaling molecules.

Protein 4.1R binds to CLASP2 and regulates dynamics, organization and attachment of microtubules to the cell cortex.

The microtubule (MT) cytoskeleton is essential for many cellular processes, including cell polarity and migration. Cortical platforms, formed by a subset of MT plus-end-tracking proteins, such as CLASP2, and non-MT binding proteins such as LL5β, attach distal ends of MTs to the cell cortex. However, the mechanisms involved in organizing these platforms have not yet been described in detail.

MAP1B regulates microtubule dynamics by sequestering EB1/3 in the cytosol of developing neuronal cells.

MAP1B, a structural microtubule (MT)-associated protein highly expressed in developing neurons, plays a key role in neurite and axon extension. However, not all molecular mechanisms by which MAP1B controls MT dynamics during these processes have been revealed. Here, we show that MAP1B interacts directly with EB1 and EB3 (EBs), two core 'microtubule plus-end tracking proteins' (+TIPs), and sequesters them in the cytosol of developing neuronal cells.

Role of CLASP2 in microtubule stabilization and the regulation of persistent motility.

In motile fibroblasts, stable microtubules (MTs) are oriented toward the leading edge of cells. How these polarized MT arrays are established and maintained, and the cellular processes they control, have been the subject of many investigations. Several MT "plus-end-tracking proteins," or +TIPs, have been proposed to regulate selective MT stabilization, including the CLASPs, a complex of CLIP-170, IQGAP1, activated Cdc42 or Rac1, a complex of APC, EB1, and mDia1, and the actin-MT crosslinking factor ACF7.

Mammalian CLASP1 and CLASP2 cooperate to ensure mitotic fidelity by regulating spindle and kinetochore function.

CLASPs are widely conserved microtubule plus-end-tracking proteins with essential roles in the local regulation of microtubule dynamics. In yeast, Drosophila, and Xenopus, a single CLASP orthologue is present, which is required for mitotic spindle assembly by regulating microtubule dynamics at the kinetochore. In mammals, however, only CLASP1 has been directly implicated in cell division, despite the existence of a second paralogue, CLASP2, whose mitotic roles remain unknown.

GSK-3 is activated by the tyrosine kinase Pyk2 during LPA1-mediated neurite retraction.

Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine kinase that is usually inactivated by serine phosphorylation in response to extracellular cues. However, GSK-3 can also be activated by tyrosine phosphorylation, but little is known about the upstream signaling events and tyrosine kinase(s) involved. Here we describe a G protein signaling pathway leading to GSK-3 activation during lysophosphatidic acid (LPA)-induced neurite retraction.

Glycogen synthase kinase-3 is activated in neuronal cells by Galpha12 and Galpha13 by Rho-independent and Rho-dependent mechanisms.

Glycogen synthase kinase-3 (GSK-3) was generally considered a constitutively active enzyme, only regulated by inhibition. Here we describe that GSK-3 is activated by lysophosphatidic acid (LPA) during neurite retraction in rat cerebellar granule neurons. GSK-3 activation correlates with an increase in GSK-3 tyrosine phosphorylation.

Regulation of neuronal cytoskeleton by lysophosphatidic acid: role of GSK-3.

Neurite retraction is a crucial process during nervous system development and neurodegeneration. This process implies reorganization of the neuronal cytoskeleton. Some bioactive lipids such as lysophosphatidic acid (LPA) induce neurite retraction.

The inhibition of phosphatidylinositol-3-kinase induces neurite retraction and activates GSK3.

It has been extensively described that neuronal differentiation involves the signalling through neurotrophin receptors to a Ras-dependent mitogen-activated protein kinase (MAPK) cascade. However, signalling pathways from other neuritogenic factors have not been well established. It has been reported that cAMP may activate protein kinase (PKA), and it has been shown that PKA-mediated stimulation of MAPK pathway regulates not only neuritogenesis but also survival.

The neurite retraction induced by lysophosphatidic acid increases Alzheimer's disease-like Tau phosphorylation.

The bioactive phospholipid lysophosphatidic acid (LPA) causes growth cone collapse and neurite retraction in neuronal cells. These changes are brought about by the action of a cell surface receptor coupled to specific G proteins that control morphology and motility through the action of a group of small GTPases, the Rho family of proteins. Many studies have focused on actin reorganization modulated by Rho-GTPases, but almost no information has been obtained concerning microtubular network reorganization after LPA-induced neurite retraction.