From tau phosphorylation to tau aggregation: what about neuronal death?

Buée, Luc; Troquier, Laetitia; Burnouf, Sylvie; Bélarbi, Karim; Jeugd, Anneke Van der; Ahmed, Tariq; Fernandez-Gomez, Francisco-José; Caillierez, Raphaëlle; Grosjean, Marie-Eve; Bégard, Séverine; Barbot, B.; Demeyer, Dominique; Obriot, Hélène; Brion, I.; Buée‐Scherrer, Valérie; Maurage, Claude Alain; Balschun, Detlef; D’Hooge, Rudi; Hamdane, Malika; Blum, David; Sergeant, Nicolas

doi:10.1042/bst0380967

Cited by 86 publications

(74 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Tau contains 80 Ser or Thr phosphorylation sites and five Tyr sites; ~71 of them can be phosphorylated under physiological or pathological conditions [23,24] . Most of the phosphorylation sites surround the microtubule-binding domains in the proline-rich region, located between regions 181-235 and 396-422 which is outside the microtubule domain in the C-terminal region.…”

Section: Tau Phosphorylationmentioning

confidence: 99%

“…Kinases Tau can be phosphorylated by 20 or more protein kinases, including four groups: proline-dependent protein kinases (PDPKs), non-PDPKs, tyrosine protein kinases, and protein kinases that phosphorylate tau on serine or threonine residues followed or not by a proline [23] . About 50% of these phosphorylation sites are canonical (Ser/ Pro, Thr/Pro) for PDPKs and the remaining sites are phosphorylated by non-PDPKs [25] .…”

Section: Phosphorylation Of Tau Is Mainly Regulated Through Kinases Amentioning

confidence: 99%

Section: Phosphorylation Of Tau Is Mainly Regulated Through Kinases Amentioning

confidence: 99%

“…About 50% of these phosphorylation sites are canonical (Ser/ Pro, Thr/Pro) for PDPKs and the remaining sites are phosphorylated by non-PDPKs [25] . The non-PDPK group includes tau-tubulin kinases 1 and 2, casein kinases 1 and 2, DYRK1A (dual-specificity tyrosine-phosphorylated and regulated kinase 1A), phosphorylase kinase, Rho kinase, PKA (protein kinase A), PKB (protein kinase B)/Akt, PKC (protein kinase C) and PKN (protein kinase novel) [23] .Tyrosine kinases are Src kinases, c-Abl and c-Met. Protein kinases that phosphorylate tau on serine or threonine residues followed or not by a proline recognize the motif SXXXS or SXXXD/E and RXRXXS/T and include GSK (glycogen synthase kinase) 3α, GSK-3β and AGC kinases [such as MSK1 (mitogen-and stress activated protein kinase)] [23] .…”

mentioning

confidence: 99%

“…The non-PDPK group includes tau-tubulin kinases 1 and 2, casein kinases 1 and 2, DYRK1A (dual-specificity tyrosine-phosphorylated and regulated kinase 1A), phosphorylase kinase, Rho kinase, PKA (protein kinase A), PKB (protein kinase B)/Akt, PKC (protein kinase C) and PKN (protein kinase novel) [23] .…”

mentioning

confidence: 99%

See 4 more Smart Citations

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

View full text Add to dashboard Cite

The accumulation of hyperphosphorylated tau is a common feature of several dementias. Tau is one of the brain microtubule-associated proteins. Here we discuss tau's functions in microtubule assembly and stabilization and with regard to its interactions with other proteins. We describe and analyze important post-translational modifications: hyperphosphorylation, ubiquitination, glycation, glycosylation, nitration, polyamination, proteolysis, acetylation, and methylation. We discuss how these post-translational modifi cations can alter tau's biological function. We analyze the role of mitochondrial health in neurodegeneration. We propose that microtubules could be a therapeutic target and review different approaches. Finally, we consider whether tau accumulation or its conformational change is related to tau-induced neurodegeneration, and propose a mechanism of neurodegeneration.Keywords: tau; phosphorylation; neurodegeneration; tauopathies; mitochondria; microtubules; tubulin; kinases; phosphatases; Alzheimer's disease ·Review· IntroductionAlzheimer 's disease (AD), first described by Alois Alzheimer more than 100 years ago [1] , is a progressive neurodegenerative disorder, characterized by an insidious onset with irreversible cognitive declines that lead to profound mental deterioration causing dementia [2] . Two major forms of lesion characterize AD: amyloid as diffuse neurotic plaques primarily composed of the Aβ peptide [3] , which are mainly insoluble deposits of protein and cellular material, and neurofibrillary tangles composed of fi lamentous hyperphosphorylated tau protein that builds up inside the neuron [4,5] .Amyloid precursor protein (APP) is a highly conserved transmembrane protein [6] believed to play a role in synapse formation, synaptic plasticity, and neuronal survival [7][8][9] .In AD, APP is cleaved by β-and γ-secretases leading to the overproduction of an abnormal proteolytic byproduct called amyloid beta (Aβ) [10] . Upon cleavage fragments of Aβ of various sizes are released from the membrane and aggregate in the brain to form the characteristic plaques seen in AD. Plaques are composed primarily of the 40 and 42 amino-acid peptide fragments Aβ40 and Aβ42, the latter being the predominant species. In addition, Aβ42 is more prone to aggregation and deposition and therefore the cause of neurotoxicity, as well as synaptic loss [11] .The second lesion in AD is formed by aggregates of the microtubule-associated protein tau, which forms intracytoplasmic neuronal inclusions or neurofibrillary tangles when hyperphosphorylated [12] . Tau is associated with neurons of the central nervous system [13] and its main biological function is promoting the in vitro assembly and stabilization of microtubules in the cytoskeleton [14,15] . Tau is a phosphoprotein that is encoded by a single gene, MAPT, located on chromosome 17q21 [16] ; alternative splicing of the gene produces six major isoforms expressed in the adult human brain [17] . Isoforms derive their names from the number of microtubule-binding repeat s...

show abstract

Section: Tau Phosphorylationmentioning

confidence: 99%

Section: Phosphorylation Of Tau Is Mainly Regulated Through Kinases Amentioning

confidence: 99%

Section: Phosphorylation Of Tau Is Mainly Regulated Through Kinases Amentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Tau-induced neurodegeneration: mechanisms and targets

Beharry

Cohen

et al. 2014

Neurosci. Bull.

View full text Add to dashboard Cite

show abstract

Transgenic Mouse Models, General Anesthetics, and Alzheimer Disease: Findings from Preclinical Studies

Bimonte

Barbieri

Nagoth

et al. 2019

General Anesthesia Research

View full text Add to dashboard Cite

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

et al. 2019

Self Cite

View full text Add to dashboard Cite

The term "propagon" is used to define proteins that may transmit misfolding in vitro, in tissues or in organisms. Among propagons, misfolded tau is thought to be involved in the pathogenic mechanisms of various "tauopathies" that include Alzheimer's disease, progressive supranuclear palsy, and argyrophilic grain disease. Here, we review the available data in the literature and point out how the prion-like tau propagation has been extended from Alzheimer's disease to tauopathies. First, in Alzheimer's disease, the progression of tau aggregation follows stereotypical anatomical stages which may be considered as spreading. The mechanisms of the propagation are now subject to intensive and controversial research. It has been shown that tau may be secreted in the interstitial fluid in an active manner as reflected by high and constant concentration of extracellular tau during Alzheimer's pathology. Animal and cell models have been devised to mimic tau seeding and propagation, and despite their limitations, they have further supported to the prion-like propagation hypothesis. Finally, such new ways of thinking have led to different therapeutic strategies in anti-tau immunotherapy among tauopathies and have stimulated new clinical trials. However, it appears that the prion-like propagation hypothesis mainly relies on data obtained in Alzheimer's disease. From this review, it appears that further studies are needed (1) to characterize extracellular tau species, (2) to find the right pathological tau species to target, (3) to follow in vivo tau pathology by brain imaging and biomarkers and (4) to interpret current clinical trial results aimed at reducing the progression of these pathologies. Such inputs will be essential to have a comprehensive view of these promising therapeutic strategies in tauopathies.

show abstract

From tau phosphorylation to tau aggregation: what about neuronal death?

Cited by 86 publications

References 45 publications

Tau-induced neurodegeneration: mechanisms and targets

Tau-induced neurodegeneration: mechanisms and targets

Transgenic Mouse Models, General Anesthetics, and Alzheimer Disease: Findings from Preclinical Studies

From the prion-like propagation hypothesis to therapeutic strategies of anti-tau immunotherapy

Contact Info

Product

Resources

About