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      Tau Protein Phosphorylated at Threonine-231 is Expressed Abundantly in the Cerebellum in Prion Encephalopathies

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          Abstract

          Background:

          Transmissible spongiform encephalopathies (TSEs) are rare neurodegenerative disorders that affect animals and humans. Bovine spongiform encephalopathy (BSE) in cattle, and Creutzfeld-Jakob Disease (CJD) in humans belong to this group. The causative agent of TSEs is called “prion”, which corresponds to a pathological form (PrP Sc) of a normal cellular protein (PrP C) expressed in nerve cells. PrP Sc is resistant to degradation and can induce abnormal folding of PrP C, and TSEs are characterized by extensive spongiosis and gliosis and the presence of PrP Sc amyloid plaques. CJD presents initially with clinical symptoms similar to Alzheimer’s disease (AD). In AD, tau aggregates and amyloid-β protein plaques are associated with memory loss and cognitive impairment in patients.

          Objective:

          In this work, we study the role of tau and its relationship with PrP Sc plaques in CJD.

          Methods:

          Multiple immunostainings with specific antibodies were carried out and analyzed by confocal microscopy.

          Results:

          We found increased expression of the glial fibrillary acidic protein (GFAP) and matrix metalloproteinase (MMP-9), and an exacerbated apoptosis in the granular layer in cases with prion disease. In these cases, tau protein phosphorylated at Thr-231 was overexpressed in the axons and dendrites of Purkinje cells and the extensions of parallel fibers in the cerebellum.

          Conclusion:

          We conclude that phosphorylation of tau may be a response to a toxic and inflammatory environment generated by the pathological form of prion.

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          Most cited references55

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          Novel proteinaceous infectious particles cause scrapie.

          After infection and a prolonged incubation period, the scrapie agent causes a degenerative disease of the central nervous system in sheep and goats. Six lines of evidence including sensitivity to proteases demonstrate that this agent contains a protein that is required for infectivity. Although the scrapie agent is irreversibly inactivated by alkali, five procedures with more specificity for modifying nucleic acids failed to cause inactivation. The agent shows heterogeneity with respect to size, apparently a result of its hydrophobicity; the smallest form may have a molecular weight of 50,000 or less. Because the novel properties of the scrapie agent distinguish it from viruses, plasmids, and viroids, a new term "prion" is proposed to denote a small proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids. Knowledge of the scrapie agent structure may have significance for understanding the causes of several degenerative diseases.
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            Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer's disease.

            The principal pathological features of Alzheimer's disease (AD) are extracellular amyloid plaques and intracellular neurofibrillary tangles, the latter composed of the microtubule-binding protein tau assembled into paired helical and straight filaments. Recent studies suggest that these pathological entities may be functionally linked, although the mechanisms by which amyloid deposition promotes pathological tau filament assembly are poorly understood. Here, we report that tau is proteolyzed by multiple caspases at a highly conserved aspartate residue (Asp421) in its C terminus in vitro and in neurons treated with amyloid-beta (Abeta) (1-42) peptide. Tau is rapidly cleaved at Asp421 in Abeta-treated neurons (within 2 h), and its proteolysis appears to precede the nuclear events of apoptosis. We also demonstrate that caspase cleavage of tau generates a truncated protein that lacks its C-terminal 20 amino acids and assembles more rapidly and more extensively into tau filaments in vitro than wild-type tau. Using a monoclonal antibody that specifically recognizes tau truncated at Asp421, we show that tau is proteolytically cleaved at this site in the fibrillar pathologies of AD brain. Taken together, our results suggest a novel mechanism linking amyloid deposition and neurofibrillary tangles in AD: Abeta peptides promote pathological tau filament assembly in neurons by triggering caspase cleavage of tau and generating a proteolytic product with enhanced polymerization kinetics.
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              Cloning and sequencing of the cDNA encoding an isoform of microtubule-associated protein tau containing four tandem repeats: differential expression of tau protein mRNAs in human brain.

              We have isolated cDNA clones encoding a 383-amino acid isoform of the human microtubule-associated protein tau. It differs from previously determined tau sequences by the presence of an additional repeat of 31 amino acids, giving four, rather than three, tandem repeats in its carboxy-terminal half. The extra repeat is encoded by a separate exon. Probes derived from cDNA clones encoding the three (type I) and four repeat (type II) tau protein isoforms detected mRNAs for both forms in all adult human brain areas examined. However, in foetal brain only type I mRNA was found. Type I and type II mRNAs were present in pyramidal cells in cerebral cortex. In the hippocampal formation, type I mRNA was found in pyramidal and granule cells; type II mRNA was detected in most, though not all, pyramidal cells but not in granule cells. These observations indicate that tau protein mRNAs are expressed in a stage- and cell-specific manner. Tau protein is found in the protease-resistant core of the paired helical filament, the major constituent of the neurofibrillary tangle in Alzheimer's disease. Taken in conjunction with previous findings, the present results indicate that both the three and four repeat-containing tau protein isoforms are present in the core of the paired helical filament.
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                Author and article information

                Journal
                J Alzheimers Dis
                J Alzheimers Dis
                JAD
                Journal of Alzheimer's Disease
                IOS Press (Nieuwe Hemweg 6B, 1013 BG Amsterdam, The Netherlands )
                1387-2877
                1875-8908
                2 April 2021
                18 May 2021
                2021
                : 81
                : 2
                : 769-785
                Affiliations
                [a ]National Dementia BioBank. Ciencias Biológicas, Facultad de Estudios Superiores, Cuautitlán, UNAM, Estado de México, México
                [b ]Physiology, Biophysics and Neuroscience, CINVESTAV, CDMX, México
                [c ] School of Engineering and Science, Tecnologico de Monterrey, Toluca, México
                [d ]Escuela Nacional de Ciencias Biológicas, Departamento Fisiología , Instituto Politécnico Nacional, CDMX, México
                [e ]CIIDIR, Durango, Instituto Politécnico Nacional , Durango, Becario COFAA, México
                [f ] School of Medicine, Medical Sciences and Nutrition, University of Aberdeen , Aberdeen, UK
                [g ]Genética, Instituto Nacional de Neurología y Neurocirugía , “Manuel Velazco Suerez” CDMX, México
                [h ]Departamento de Neurocirugía , Centro Especializado en Neurocirugía y Neurociencias, México, (CENNM), CDMX, México
                [i ]Departamento de Bioingeniería , Unidad Profesional Interdisciplinaria de Biotecnología del Instituto Politécnico Nacional, Gustavo A. Madero, México
                [j ]Neuroscience Research Laboratory, Faculty of Health Sciences, Pontificia Universidad Catolica Madre y Maestra , Santiago de los Caballeros, Dominican Republic
                [k ]National Brain Bank. Universidad Nacional Pedro Henríquez Ureña , Santo Domingo, Dominican Republic
                Author notes
                [* ]Correspondence to: José Luna-Muñoz, National Dementia BioBank. Ciencias Biológicas, Facultad de Estudios Superiores, Cuautitlán, UNAM, Estado de México, México. Tel.: +521 5527080653, E-mail: jluna_tau67@ 123456comunidad.unam.mx and Mar Pacheco-Herrero, Neuroscience Research Laboratory, Faculty of Health Sciences, Pontificia Universidad Catolica Madre y Maestra, Santiago de los Caballeros, Dominican Republic, E-mail: mpacheco@ 123456pucmm.edu.do .
                Article
                JAD201308
                10.3233/JAD-201308
                8203236
                33814431
                608ab06b-2cf9-4722-add6-0acb1d854b87
                © 2021 – The authors. Published by IOS Press

                This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 9 March 2021
                Categories
                Research Article

                cerebellum,neuronal death,prion encephalopathy,prion protein, tau protein

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