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Glial fibrillary tangles and JAK/STAT-mediated glial and neuronal cell death in a Drosophila model of glial tauopathy.

ABSTRACT: A subset of neurodegenerative tauopathies is characterized by abundant filamentous inclusions of hyperphosphorylated tau in both neurons and glia. Although the contribution of neuronal tau to behavioral changes and neuronal loss in neurodegenerative diseases has been studied extensively, the functional consequences of tau deposition in glial cells have been less well characterized. To investigate the role of abnormal tau accumulation and aggregation in glial cells, we created a Drosophila model of glial tauopathy by expressing human wild-type tau in adult fly glial cells. Glial expression of tau resulted in robust aggregation of phosphorylated tau into fibrillary inclusions similar to human glial tangles. Tangle formation was accompanied by shortened lifespan and age-dependent apoptotic cell death of both glia and neurons. Genetic manipulation of Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling modified toxicity of glial tau. We also identified a synergistic interaction of combined tau expression in neurons and glial cells. In summary, we present a genetically tractable model of glial fibrillary tau tangle formation and identify JAK/STAT signaling as mediating the death of both glia and neurons in this model.

SUBMITTER: Colodner KJ

PROVIDER: S-EPMC3073608 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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Glial fibrillary tangles and JAK/STAT-mediated glial and neuronal cell death in a Drosophila model of glial tauopathy.

Colodner Kenneth J KJ Feany Mel B MB

The Journal of neuroscience : the official journal of the Society for Neuroscience 20101201 48

A subset of neurodegenerative tauopathies is characterized by abundant filamentous inclusions of hyperphosphorylated tau in both neurons and glia. Although the contribution of neuronal tau to behavioral changes and neuronal loss in neurodegenerative diseases has been studied extensively, the functional consequences of tau deposition in glial cells have been less well characterized. To investigate the role of abnormal tau accumulation and aggregation in glial cells, we created a Drosophila model ...[more]

PMID: 21123557

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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

Glial fibrillary tangles and JAK/STAT-mediated glial and neuronal cell death in a Drosophila model of glial tauopathy.

Publications

Glial fibrillary tangles and JAK/STAT-mediated glial and neuronal cell death in a Drosophila model of glial tauopathy.

Similar Datasets

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