Open Access
Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy
(Springer, 2020) Ferrer, Isidro; Andrés Benito, Pol; Zelaya Huerta, María Victoria; Erro Aguirre, María Elena; Carmona, Margarita; Ausín, Karina; Lachén Montes, Mercedes; Fernández Irigoyen, Joaquín; Santamaría Martínez, Enrique; Río, José Antonio del; Ciencias de la Salud; Osasun Zientziak; Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa
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.
Open Access
Is the phenotype designation by PSP-MDS criteria stable throughout the disease course and consistent with tau distribution?
(Frontiers Media, 2022) Sánchez Ruiz de Gordoa, Javier; Zelaya Huerta, María Victoria; Tellechea-Aramburo, Paula; Acha Santamaría, Blanca; Roldán, Miren; López Molina, Carlos; Coca, Valle; Galbete Jiménez, Arkaitz; Mendióroz Iriarte, Maite; Erro Aguirre, María Elena; Estadística, Informática y Matemáticas; Estatistika, Informatika eta Matematika
Introduction: the MDS-PSP criteria have shown high sensitivity for the PSP diagnosis, but do not discriminate the phenotype diversity. Our purpose was to search for anatomopathological differences among PSP phenotypes resulting from the application of the MDS-PSP criteria comparing with the previous ones. Methods: thirty-four PSP cases from a single brain bank were retrospectively classified according to the criteria used by Respondek et al. in 2014 and the PSP-MDS criteria at 3 years (MDS-3y), 6 years (MDS-6y) and at the last clinical evaluation before death (MDS-last). Semiquantitative measurement of total, cortical and subcortical tau load was compared. For comparative analysis, PSP-Richardson syndrome and PSP postural instability were grouped (PSP-RS/PI) as well as the PSP atypical cortical phenotypes (PSP-Cx). Results: applying the Respondek's criteria, PSP phenotypes were distributed as follow: 55.9% PSP-RS/PI, 26.5% PSP-Cx, 11.8% PSP-Parkinsonism (PSP-P), and 5.9% PSP-Cerebellum. PSP-RS/PI and PSP-Cx had a higher total tau load than PSP-P; PSP-Cx showed a higher cortical tau load than PSP-RS/PI and PSP-P; and PSP-RS/PI had a higher subcortical tau load than PSP-P. Applying the MDS-3y, MDS-6y and MDS-last criteria; the PSP-RS/PI group increased (67.6, 70.6 and 70.6% respectively) whereas the PSP-Cx group decreased (8.8, and 8.8 and 11.8%). Then, only differences in total and subcortical tau burden between PSP-RS/PI and PSP-P were observed. Interpretation: after the retrospective application of the new MDS-PSP criteria, total and subcortical tau load is higher in PSP-RS/PI than in PSP-P whereas no other differences in tau load between phenotypes were found, as a consequence of the loss of phenotypic diversity.

Zelaya Huerta, María Victoria

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