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  1. Article ; Online: Tau: More than a microtubule-binding protein in neurons.

    Alonso, Alejandra Del Carmen / El Idrissi, Abdeslem / Candia, Robert / Morozova, Viktoriya / Kleiman, Frida Esther

    Cytoskeleton (Hoboken, N.J.)

    2023  Volume 81, Issue 1, Page(s) 71–77

    Abstract: Tau protein was discovered as a microtubule-associated protein nearly 50 years ago, and our understanding of tau has revolved around that role. Even with tau's rise to stardom as a central player in neurodegenerative disease, therapeutic efforts have ... ...

    Abstract Tau protein was discovered as a microtubule-associated protein nearly 50 years ago, and our understanding of tau has revolved around that role. Even with tau's rise to stardom as a central player in neurodegenerative disease, therapeutic efforts have largely been targeted toward cytoskeletal changes. While some studies hinted toward non-cytoskeletal roles for tau, it is only fairly recently that these ideas have begun to receive considerable attention. Many new binding partners for tau have been identified, including DNA, RNA, RNA-binding proteins, some receptors, and other tau molecules. The diversity of tau binding partners coupled with the discovery of tau other than axonal compartments such as nucleus, dendrites, and synapses have led to the proposal of novel functions for tau in roles such as nuclear stability, cell signaling, transcriptional processing, and protein synthesis. Tau self-assembly in particular has made an impact, leading to the hypothesis that a prion-like function of hyperphosphorylated tau is central to tauopathies. With tau emerging as a multifaceted protein that operates in many parts of the cell and with many molecular partners, the field of tau biology is primed for discoveries that can provide new perspectives on both the unique biochemistry of tau and the nature of devastating neurological diseases.
    MeSH term(s) Humans ; tau Proteins/chemistry ; Neurodegenerative Diseases/metabolism ; Carrier Proteins/metabolism ; Microtubules/metabolism ; Neurons/metabolism ; Phosphorylation
    Chemical Substances tau Proteins ; Carrier Proteins
    Language English
    Publishing date 2023-10-11
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2534372-5
    ISSN 1949-3592 ; 1949-3584
    ISSN (online) 1949-3592
    ISSN 1949-3584
    DOI 10.1002/cm.21795
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Importin-Mediated Pathological Tau Nuclear Translocation Causes Disruption of the Nuclear Lamina, TDP-43 Mislocalization and Cell Death.

    Candia, Robert F / Cohen, Leah S / Morozova, Viktoriya / Corbo, Christopher / Alonso, Alejandra D

    Frontiers in molecular neuroscience

    2022  Volume 15, Page(s) 888420

    Abstract: Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of ... ...

    Abstract Tau is a cytosolic protein that has also been observed in the nucleus, where it has multiple proposed functions that are regulated by phosphorylation. However, the mechanism underlying the nuclear import of tau is unclear, as is the contribution of nuclear tau to the pathology of tauopathies. We have previously generated a pathological form of tau, PH-tau (pseudophosphorylation mutants S199E, T212E, T231E, and S262E) that mimics AD pathological behavior in cells,
    Language English
    Publishing date 2022-05-03
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2022.888420
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Normal and Pathological Tau Uptake Mediated by M1/M3 Muscarinic Receptors Promotes Opposite Neuronal Changes.

    Morozova, Viktoriya / Cohen, Leah S / Makki, Ali El-Hadi / Shur, Alison / Pilar, Guillermo / El Idrissi, Abdeslem / Alonso, Alejandra D

    Frontiers in cellular neuroscience

    2019  Volume 13, Page(s) 403

    Abstract: The microtubule associated protein tau is mainly found in the cell's cytosol but recently it was also shown in the extracellular space. In neurodegenerative diseases, like Alzheimer's disease (AD), pathological tau spreads from neuron to neuron enhancing ...

    Abstract The microtubule associated protein tau is mainly found in the cell's cytosol but recently it was also shown in the extracellular space. In neurodegenerative diseases, like Alzheimer's disease (AD), pathological tau spreads from neuron to neuron enhancing neurodegeneration. Here, we show that HEK293 cells and neurons in culture uptake extracellular normal and pathological Tau. Muscarinic receptor antagonists atropine and pirenzepine block 80% this uptake. CHO cells do not express these receptors therefore cannot uptake tau, unless transfected with M1 and/or M3 receptor. These results strongly suggest that muscarinic receptors mediate this process. Uptake of normal tau in neurons enhances neuronal process formation but a pseudophosphorylated form of tau (pathological human tau, PH-Tau) disrupts them and accumulates in the somatodendritic compartment. AD hyperphosphorylated tau (AD P-Tau) has similar effects as PH-Tau on cultured neurons. Addition of either PH-Tau or AD P-tau to neuronal cultures induced microglial activation. In conclusion, uptake of extracellular tau is mediated by muscarinic receptors with opposite effects: normal tau stabilizes neurites; whereas pathological tau disrupts this process leading to neurodegeneration.
    Language English
    Publishing date 2019-09-04
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2019.00403
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article: Hyperphosphorylation of Tau Associates With Changes in Its Function Beyond Microtubule Stability.

    Alonso, Alejandra D / Cohen, Leah S / Corbo, Christopher / Morozova, Viktoriya / ElIdrissi, Abdeslem / Phillips, Greg / Kleiman, Frida E

    Frontiers in cellular neuroscience

    2018  Volume 12, Page(s) 338

    Abstract: Tau is a neuronal microtubule associated protein whose main biological functions are to promote microtubule self-assembly by tubulin and to stabilize those already formed. Tau also plays an important role as an axonal microtubule protein. Tau is an ... ...

    Abstract Tau is a neuronal microtubule associated protein whose main biological functions are to promote microtubule self-assembly by tubulin and to stabilize those already formed. Tau also plays an important role as an axonal microtubule protein. Tau is an amazing protein that plays a key role in cognitive processes, however, deposits of abnormal forms of tau are associated with several neurodegenerative diseases, including Alzheimer disease (AD), the most prevalent, and Chronic Traumatic Encephalopathy (CTE) and Traumatic Brain Injury (TBI), the most recently associated to abnormal tau. Tau post-translational modifications (PTMs) are responsible for its gain of toxic function. Alonso et al. (1996) were the first to show that the pathological tau isolated from AD brains has prion-like properties and can transfer its toxic function to the normal molecule. Furthermore, we reported that the pathological changes are associated with tau phosphorylation at Ser199 and 262 and Thr212 and 231. This pathological version of tau induces subcellular mislocalization in cultured cells and neurons, and translocates into the nucleus or accumulated in the perinuclear region of cells. We have generated a transgenic mouse model that expresses pathological human tau (PH-Tau) in neurons at two different concentrations (4% and 14% of the total endogenous tau). In this model, PH-Tau causes cognitive decline by at least two different mechanisms: one that involves the cytoskeleton with axonal disruption (at high concentration), and another in which the apparent neuronal morphology is not grossly affected, but the synaptic terminals are altered (at lower concentration). We will discuss the putative involvement of tau in proteostasis under these conditions. Understanding tau's biological activity on and off the microtubules will help shed light to the mechanism of neurodegeneration and of normal neuronal function.
    Language English
    Publishing date 2018-10-09
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2018.00338
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article: Nuclear Tau, p53 and Pin1 Regulate PARN-Mediated Deadenylation and Gene Expression.

    Baquero, Jorge / Varriano, Sophia / Ordonez, Martha / Kuczaj, Pawel / Murphy, Michael R / Aruggoda, Gamage / Lundine, Devon / Morozova, Viktoriya / Makki, Ali Elhadi / Alonso, Alejandra Del C / Kleiman, Frida E

    Frontiers in molecular neuroscience

    2019  Volume 12, Page(s) 242

    Abstract: While nuclear tau plays a role in DNA damage response (DDR) and chromosome relaxation, the mechanisms behind these functions are not fully understood. Here, we show that tau forms complex(es) with factors involved in nuclear mRNA processing such as tumor ...

    Abstract While nuclear tau plays a role in DNA damage response (DDR) and chromosome relaxation, the mechanisms behind these functions are not fully understood. Here, we show that tau forms complex(es) with factors involved in nuclear mRNA processing such as tumor suppressor p53 and poly(A)-specific ribonuclease (PARN) deadenylase. Tau induces PARN activity in different cellular models during DDR, and this activation is further increased by p53 and inhibited by tau phosphorylation at residues implicated in neurological disorders. Tau's binding factor Pin1, a mitotic regulator overexpressed in cancer and depleted in Alzheimer's disease (AD), also plays a role in the activation of nuclear deadenylation. Tau, Pin1 and PARN target the expression of mRNAs deregulated in AD and/or cancer. Our findings identify novel biological roles of tau and toxic effects of hyperphosphorylated-tau. We propose a model in which factors involved in cancer and AD regulate gene expression by interactions with the mRNA processing machinery, affecting the transcriptome and suggesting insights into alternative mechanisms for the initiation and/or developments of these diseases.
    Language English
    Publishing date 2019-10-15
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2452967-9
    ISSN 1662-5099
    ISSN 1662-5099
    DOI 10.3389/fnmol.2019.00242
    Database MEDical Literature Analysis and Retrieval System OnLINE

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