Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings

Erro, María Elena; Zelaya, María Victoria; Mendioroz, Maite; Larumbe, R; Ortega‐Cubero, Sara; Lanciego, José L.; Lladó, Albert; Cabada, T.; Tuñón, T; García-Bragado, F.; Luquín, M.R.; Pástor, Pau; Ferrer, Isidre

doi:10.1007/s00415-019-09414-w

Cited by 21 publications

(30 citation statements)

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“…Based on the neuropathological description of the prevalence and distribution of globular glial inclusions in frontal, motor and temporal cortices, this case is suggestive of GGT Type III [11]. Four GGT cases with the P301L mutation from two independent pedigrees have recently been reported and although further pathological subtyping was difficult, three cases were suggestive of Type I and one case had features of Type I and III pathology [12]. Finally, an earlier study reported a case with an R5H missense mutation on exon 1 with predominant globular oligodendroglial inclusions in the white matter underlying the frontal and temporal cortices, which is likely to meet criteria for GGT Type I [13].…”

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confidence: 88%

“…Direct comparison of GGT Type III cases with a mutation in MAPT with all other GGT Type III cases (n = 7) revealed those with a mutation (n = 3) were 17 years younger at diagnosis (median 54 [54-57] years vs. 71 [66-86] years; P < 0.02). Disease duration varied from 1 to 9 years in GGT Type III cases with a mutation in MAPT, and did not differ from all other GGT Type III cases (median 4 [3][4][5][6][7][8][9] years vs. 5 [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] years; P = 0.67). The earlier age at symptom onset and diagnosis in cases with mutations in MAPT is well recognized, although the mechanism for this remains unclear.…”

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confidence: 99%

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Are mutations in MAPT associated with GGT type III?

Forrest

Halliday

Shepherd

et al. 2019

Neuropathology Appl Neurobio

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confidence: 88%

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confidence: 99%

Are mutations in MAPT associated with GGT type III?

Forrest

Halliday

Shepherd

et al. 2019

Neuropathology Appl Neurobio

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“…The majority of GGTs are sporadic [1], but a few familial cases have been reported linked to different mutations in the microtubule-associated protein tau gene (MAPT): N296H in exon 10 [62], R5H in exon 1 [56], K317M in exon 11 [40,135], K317N in exon 11 [111], P301L in exon 10 [10,44,112], and IVS10 + 16 [44]. Recently, we have reported five new cases of familial GGT from two unrelated pedigrees bearing the P301T mutation in MAPT [28]. A typical 4Rtau band pattern consisting of two bands of 68 kDa and 64 kDa, and several lower bands of about 35 kDa, is also found in familial GGTs [28,111,135].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

“…Recently, we have reported five new cases of familial GGT from two unrelated pedigrees bearing the P301T mutation in MAPT [28]. A typical 4Rtau band pattern consisting of two bands of 68 kDa and 64 kDa, and several lower bands of about 35 kDa, is also found in familial GGTs [28,111,135]. GGT has been classified according to three subtypes [1].…”

Section: Electronic Supplementary Materialsmentioning

confidence: 99%

“…For these purposes, we focused the study on recently reported genetic GGT cases from two unrelated pedigrees bearing the P301T mutation in MAPT [28]. For comparative purposes, we also analysed one sporadic GGT presenting with primary progressive aphasia [case 1,38], and another genetic GGT case manifested with frontotemporal dementia, parkinsonism, and motor neuron disease linked to K317M mutation in MAPT [135].…”

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confidence: 99%

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Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy

et al. 2020

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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 OLIG2 mRNA, 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. Keywords Globular glial tauopathy • Tau • Astrogliopathy • Oligodendrogliopathy • Phosphoproteome • Seeding and spreading alien hand, myoclonus, and dystonic movements...

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Association Between Globular Glial Tauopathies and Frontotemporal Dementia—Expanding the Spectrum of Gliocentric Disorders

2021

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IMPORTANCE Globular glial tauopathies (GGTs), as defined by a consensus study in 2013, belong to the group of frontotemporal lobar degenerations and expand the spectrum of glial-predominant neurodegenerative diseases. Three neuropathological subtypes of GGT (types I-III) are characterized by phosphorylated tau-immunopositive inclusions that are predominantly in oligodendroglia and/or astroglia in the frontal, temporal, and/or precentral cortices. Type II is largely restricted to the corticospinal system. The low incidence of GGT (<10% of cases of frontotemporal lobar degeneration with tau pathology), together with its unusual combination of neuronal and nonneuronal pathology, has hindered identification and accurate diagnosis. This review collated clinical, demographic, neuropathological, and genetic data from 88 published GGT cases identified on PubMed to examine the association between GGT and frontotemporal dementia and associated disorders.

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Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings

Cited by 21 publications

References 21 publications

Are mutations in MAPT associated with GGT type III?

Are mutations in MAPT associated with GGT type III?

Familial globular glial tauopathy linked to MAPT mutations: molecular neuropathology and seeding capacity of a prototypical mixed neuronal and glial tauopathy

Association Between Globular Glial Tauopathies and Frontotemporal Dementia—Expanding the Spectrum of Gliocentric Disorders

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