Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy
| dc.contributor.author | Ferrer, Isidro | |
| dc.contributor.author | Andrés Benito, Pol | |
| dc.contributor.author | Zelaya Huerta, María Victoria | |
| dc.contributor.author | Erro Aguirre, María Elena | |
| dc.contributor.author | Carmona, Margarita | |
| dc.contributor.author | Ausín, Karina | |
| dc.contributor.author | Lachén Montes, Mercedes | |
| dc.contributor.author | Fernández Irigoyen, Joaquín | |
| dc.contributor.author | Santamaría Martínez, Enrique | |
| dc.contributor.author | Río, José Antonio del | |
| dc.contributor.department | Ciencias de la Salud | es_ES |
| dc.contributor.department | Osasun Zientziak | eu |
| dc.contributor.funder | Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa | es |
| dc.date.accessioned | 2020-05-21T09:23:40Z | |
| dc.date.available | 2020-05-21T09:23:40Z | |
| dc.date.issued | 2020 | |
| dc.description.abstract | Globular glial tauopathy (GGT) is a progressive neurodegenerative disease involving the grey matter and white matter (WM) and characterized by neuronal deposition of hyper-phosphorylated, abnormally conformed, truncated, oligomeric 4Rtau in neurons and in glial cells forming typical globular astrocyte and oligodendrocyte inclusions (GAIs and GOIs, respectively) and coiled bodies. Present studies centre on four genetic GGT cases from two unrelated families bearing the P301T mutation in MAPT and one case of sporadic GGT (sGGT) and one case of GGT linked to MAPT K317M mutation, for comparative purposes. Clinical and neuropathological manifestations and biochemical profiles of phospho-tau are subjected to individual variations in patients carrying the same mutation, even in carriers of the same family, independently of the age of onset, gender, and duration of the disease. Immunohistochemistry, western blotting, transcriptomic, proteomics and phosphoproteomics, and intra-cerebral inoculation of brain homogenates to wild-type (WT) mice were the methods employed. In GGT cases linked to MAPT P301T mutation, astrocyte markers GFAP, ALDH1L1, YKL40 mRNA and protein, GJA1 mRNA, and AQ4 protein are significantly increased; glutamate transporter GLT1 (EAAT2) and glucose transporter (SLC2A1) decreased; mitochondrial pyruvate carrier 1 (MPC1) increased, and mitochondrial uncoupling protein 5 (UCP5) almost absent in GAIs in frontal cortex (FC). Expression of oligodendrocyte markers OLIG1 and OLIG2mRNA, and myelin-related genes MBP, PLP1, CNP, MAG, MAL, MOG, and MOBP are significantly decreased in WM; CNPase, PLP1, and MBP antibodies reveal reduction and disruption of myelinated fibres; and SMI31 antibodies mark axonal damage in the WM. Altered expression of AQ4, GLUC-t, and GLT-1 is also observed in sGGT and in GGT linked to MAPT K317M mutation. These alterations point to primary astrogliopathy and oligodendrogliopathy in GGT. In addition, GGT linked to MAPT P301T mutation proteotypes unveil a proteostatic imbalance due to widespread (phospho)proteomic dearrangement in the FC and WM, triggering a disruption of neuron projection morphogenesis and synaptic transmission. Identification of hyper-phosphorylation of variegated proteins calls into question the concept of phospho-tau-only alteration in the pathogenesis of GGT. Finally, unilateral inoculation of sarkosyl-insoluble fractions of GGT homogenates from GGT linked to MAPT P301T, sGGT, and GGT linked to MAPT K317M mutation in the hippocampus, corpus callosum, or caudate/putamen in wild-type mice produces seeding, and time- and region-dependent spreading of phosphorylated, non-oligomeric, and non-truncated 4Rtau and 3Rtau, without GAIs and GOIs but only of coiled bodies. These experiments prove that host tau strains are important in the modulation of cellular vulnerability and phenotypes of phospho-tau aggregates. | en |
| dc.description.sponsorship | The project leading to these results received funding from 'La Caixa' Foundation under the agreement LCF/PR/HR19/52160007. The study was also supported by the Ministry of Economy and Competiveness (cofunded by European Regional Development Fund, ERDF, a way to build Europe): FIS PI17/000809 and IFI15/00035 fellowship to PA-B; and co-financed by ERDF under the program Interreg Poctefa: RedPrion 148/16; the Intra-CIBERNED 2019 collaborative project. ML-M was supported by a predoctoral fellowship from the Public University of Navarra (UPNA). The Proteomics Unit of Navarrabiomed is a member of Proteored, PRB3-ISCIII, and is supported by Grant PT17/0019/009, of the PE I + D + I 2013–2016 funded by ISCIII and FEDER. | en |
| dc.format.extent | 37 p. | |
| dc.format.mimetype | application/pdf | en |
| dc.identifier.doi | 10.1007/s00401-019-02122-9 | |
| dc.identifier.issn | 0001-6322 | |
| dc.identifier.uri | https://academica-e.unavarra.es/handle/2454/36951 | |
| dc.language.iso | eng | en |
| dc.publisher | Springer | en |
| dc.relation.ispartof | Acta Neuropathologica, 2020, 139, 735-771 | en |
| dc.relation.publisherversion | https://doi.org/10.1007/s00401-019-02122-9 | |
| dc.rights | © The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. | en |
| dc.rights.accessRights | info:eu-repo/semantics/openAccess | |
| dc.rights.uri | https://creativecommons.org/licenses/by/4.0/ | |
| dc.subject | Globular glial tauopathy | en |
| dc.subject | Tau | en |
| dc.subject | Astrogliopathy | en |
| dc.subject | Oligodendrogliopathy | en |
| dc.subject | Phosphoproteome | en |
| dc.subject | Seeding and spreading | en |
| dc.title | Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy | en |
| dc.type | info:eu-repo/semantics/article | |
| dc.type.version | info:eu-repo/semantics/publishedVersion | |
| dspace.entity.type | Publication | |
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