Neurofibrillary Degeneration in Progressive Supranuclear Palsy and Corticobasal Degeneration

Sergeant, Nicolas; Wattez, A.; Delacourte, André

doi:10.1046/j.1471-4159.1999.0721243.x

Cited by 260 publications

(158 citation statements)

References 27 publications

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“…1 A). This protein smear is characteristic of aggregated tau protein in human tauopathies (Norlund et al, 1999;Sergeant et al, 1999;Zemaitaitis et al, 2000;Zhukareva et al, 2002) and is demonstrated in Figure 1 B, in which we loaded an increased amount of cross-linked proteins from P30lL animals on gels in conjunction with cross-linked PHF from the Sarkosyl-insoluble fraction of AD temporal cortex. Both P301L tau transgenic mice and AD tissue exhibit a smear of high-molecular mass crosslinked tau protein, with some cross-linked tau remaining in the stacking gel (Fig.…”

Section: Transglutaminase-catalyzed Cross-links In Phosphorylated Taumentioning

confidence: 72%

Tau Protein Is Cross-Linked by Transglutaminase in P301L Tau Transgenic Mice

Halverson¹,

Lewis²,

Frausto³

et al. 2005

J. Neurosci.

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The microtubule-associated protein tau is highly soluble under physiological conditions. However, in tauopathies, tau protein aggregates into insoluble filaments and neurofibrillary tangles (NFTs). The mechanisms underlying the formation of tau filaments and NFTs in tauopathies remain unclear. Several lines of evidence suggest that transglutaminase may cross-link tau into stable, insoluble aggregates, leading to the formation of NFTs in Alzheimer's disease and progressive supranuclear palsy. To further determine the contribution of transglutaminase in the formation of NFTs, we compared the levels of cross-linked tau protein from P301L tau transgenic mice that develop NFTs to four-repeat wild-type (4RWT) tau transgenic and nontransgenic mice that do not develop NFT pathology. Immunoprecipitation and immunoblotting experiments show that transglutaminase cross-links phosphorylated tau in the hindbrain of P301L tau transgenic mice but not in mice overexpressing 4RWT tau and nontransgenic mice. Cross-linked, phosphorylated tau from P301L tau transgenic mice runs as high-molecular mass aggregates on Western blots, similar to cross-linked tau from paired helical filaments of Alzheimer's disease. We also used double-label immunofluorescence to demonstrate colocalization of PHF-1-immunoreactive tau and the transglutaminase-catalyzed cross-link in the hindbrain, spinal cord, and cortex of P301L tau transgenic mice. In the spinal cord, 87% of PHF-1-labeled cells colocalize with the transglutaminase-catalyzed cross-link. Additionally, transglutaminase enzymatic activity is significantly elevated in the spinal cord of P301L tau transgenic mice. These studies further implicate transglutaminase in the formation and/or stabilization of NFT and paired helical filaments and provide a model system to investigate the therapeutic potential of transglutaminase inhibitors in tauopathies.

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Section: Transglutaminase-catalyzed Cross-links In Phosphorylated Taumentioning

confidence: 72%

Tau Protein Is Cross-Linked by Transglutaminase in P301L Tau Transgenic Mice

Halverson¹,

Lewis²,

Frausto³

et al. 2005

J. Neurosci.

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“…However, the ability of intronic mutations to induce dominant familial tauopathy syndromes by creating an imbalance between three and four-repeat tau isoforms [70][71][72] also demonstrated that tau toxicity is dependent on an extremely subtle interplay between the parameters associated with MT:tau binding, tau:tau binding, and tau hyperphosphorylation.…”

Section: Tau -The Amyloid Cascade Hypothesis Is Incompletementioning

confidence: 99%

Untangling the role of tau in Alzheimer’s disease: A unifying hypothesis

Bhatia

Hall

2013

Translational Neuroscience

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Recent investigations into the etiology and pathogenesis of Alzheimer's disease (AD) in the past few years have expanded to include previously unexplored and/or disconnected aspects of AD and related conditions at both the cellular and systemic levels of organization. These include how AD-associated abnormalities affect the cell cycle and neuronal differentiation state and how they recruit signal transduction, membrane trafficking and protein transcytosis mechanisms to produce a neurotoxic syndrome capable of spreading itself throughout the brain. The recent expansion of AD research into intercellular and new aspects of cellular degenerative mechanisms is causing a systemic re-evaluation of AD pathogenesis, including the roles played by well-studied elements, such as the generation of Aβ and tau protein aggregates. It is also changing our view of neurodegenerative diseases as a whole. Here we propose a conceptual framework to account for some of the emerging aspects of the role of tau in AD pathogenesis.

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“…Others have correlated the distribution of neurofibrillary tangles of Tau in AD brains with trans-synaptic distance from the affected areas (9). A similar spread affecting different subsets of neurons has been observed in other sporadic tauopathies, such as progressive supranuclear palsy (10). It is unknown why Tau misfolding progresses through the brain, whether it is a sequence of cell autonomous processes or whether a toxic factor is involved.…”

mentioning

confidence: 94%