Dataset Information

Clinical, radiologic, and pathologic features of the globular glial tauopathy subtype of frontotemporal lobar degeneration in right temporal variant frontotemporal dementia with salient features of Geschwind syndrome.

ABSTRACT: Globular Glial Tauopathy (GGT) is a rare form of Frontotemporal Lobar Degeneration (FTLD) consisting of 4-repeat tau globular inclusions in astrocytes and oligodendrocytes. We present the pathological findings of GGT in a previously published case of a 73-year-old woman with behavioral symptoms concerning for right temporal variant frontotemporal dementia with initial and salient features of Geschwind syndrome. Clinically, she lacked motor abnormalities otherwise common in previously published GGT cases. Brain MRI showed focal right anterior temporal atrophy (indistinguishable from five FTLD-TDP cases) and subtle ipsilateral white matter signal abnormalities. Brain autopsy showed GGT type III and Alzheimer's neuropathologic changes. .

SUBMITTER: Josephy-Hernandez S

PROVIDER: S-EPMC9682487 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Clinical, radiologic, and pathologic features of the globular glial tauopathy subtype of frontotemporal lobar degeneration in right temporal variant frontotemporal dementia with salient features of Geschwind syndrome.

Josephy-Hernandez Sylvia S Brickhouse Michael M Champion Samantha S Kim David Dongkyung DD Touroutoglou Alexandra A Frosch Matthew M Dickerson Bradford C BC

Neurocase 20220801 4

Globular Glial Tauopathy (GGT) is a rare form of Frontotemporal Lobar Degeneration (FTLD) consisting of 4-repeat tau globular inclusions in astrocytes and oligodendrocytes. We present the pathological findings of GGT in a previously published case of a 73-year-old woman with behavioral symptoms concerning for right temporal variant frontotemporal dementia with initial and salient features of Geschwind syndrome. Clinically, she lacked motor abnormalities otherwise common in previously published G ...[more]

PMID: 36251576

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Project description:Tauopathies are neurodegenerative disorders characterized by aggregation of microtubule associated tau protein in neurons and glia. They are clinically and pathologically heterogeneous depending on the isoform of tau protein that accumulates (three or four 31-to-32-amino-acid repeats [3R or 4R] in the microtubule binding domain), as well as the cellular and neuroanatomical distribution of tau pathology. Growing evidence suggests that distinct tau conformers may contribute to the characteristic features of various tauopathies. Globular glial tauopathy (GGT) is a rare 4R tauopathy with globular cytoplasmic inclusions within neurons and glial cells. Given the unique cellular distribution and morphology of tau pathology in GGT, we sought to determine if tau species in GGT had distinctive biological properties. To address this question, we performed seeding analyses with postmortem brain tissues using a commercial tau biosensor cell line. We found that brain lysates from GGT cases had significantly higher seeding competency than other tauopathies, including corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Alzheimer's disease (AD). The robust seeding activity of GGT brain lysates was independent of phosphorylated tau burden and diminished upon removal of tau from samples, suggesting that seeding properties were indeed mediated by tau in the lysates. In addition, cellular inclusions in the tau biosensor cell line induced by GGT had a distinct, globular morphology that was markedly different from inclusions induced by other tauopathies, further highlighting the unique nature of tau species in GGT. Characterization of different tau species in GGT showed that detergent-insoluble, fibril-like tau contained the highest seeding activity, as reflected in its ability to increase tau aggregation in primary glial cultures. Taken together, our data suggest that unique seeding properties differentiate GGT-tau from other tauopathies, which provides new insight into pathogenic heterogeneity of primary neurodegenerative tauopathies.

Project description: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.

Dataset Information

Clinical, radiologic, and pathologic features of the globular glial tauopathy subtype of frontotemporal lobar degeneration in right temporal variant frontotemporal dementia with salient features of Geschwind syndrome.

Publications

Clinical, radiologic, and pathologic features of the globular glial tauopathy subtype of frontotemporal lobar degeneration in right temporal variant frontotemporal dementia with salient features of Geschwind syndrome.

Similar Datasets

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