Phosphorylation of specific sets of tau isoforms reflects different neurofibrillary degeneration processes

Abstract

Tau proteins are the basic components of filaments that accumulate within neurons during neurofibrillary degeneration, a degenerating process with disease-specific phenotypes. This specificity is likely to be sustained by both phosphorylation state and isoform content of tau aggregates that form neuronal inclusions. In the present study, characterization of tau isoforms involved in neurofibrillary degeneration in Alzbeimer's disease, Pick's disease, corticobasal degeneration and progressive supranuclear palsy was performed. Both analyses by immunoblotting using specific tau antibodies and cell transfection by tau isoform cDNAs allowed us to demonstrate the aggregation of (1) the six hyperpbosphorylated tau isoforms in Alzheimer's disease, (2) tau isoforms without exon 10-encoding sequence in Pick's disease and (3) hyperphosphorylated exon 10-tau isoforms in corticobasal degeneration and progressive supranuclear palsy. Thus, neurofibrillary degeneration phenotypes are likely to be related to the phosphorylation of different combinations of tau isoforms (with and/or without exon 10-encoding sequence) in subpopulations of neurons.

Tau Phosphorylation at Serine 396 and Serine 404 by Human Recombinant Tau Protein Kinase II Inhibits Tau's Ability to Promote Microtubule Assembly

“…We show that TPK II-mediated tau phosphorylation at Ser-396 and Ser-404 is primarily responsible for the loss of tau function in MT assembly and dissociation of tau from microtubules. These results are discussed with regard to TPK II as a potential target for inhibiting initiation of tau hyperphosphorylation and the implications for tauopathies endowed with Ser-396 and Ser-404 phosphoepitopes (20,21).…”

“…These neurodegenerative diseases include progressive supranuclear palsy, corticobasal degeneration, Down's syndrome, frontotemporal dementia and Parkinsonism linked to chromosome 17, and Pick's disease (20). Recent studies show that these various phenotypes might be the result of phosphorylation of specific tau isoforms in different nerve cells in distinct brain regions (21).…”

The Microtubule-Dissociating Tau in Neurological Disorders

“…In addition, aggregated tau proteins in Pick's disease are not detected by the monoclonal antibody 12E8 raised against the phosphorylated residue Ser262/Ser356, whereas this phosphorylation site is detected in other neurodegenerative disorders. The lack of phosphorylation at Ser262 and Ser356 sites is likely to be related to either a kinase is not active in neurons that degenerate in Pick's disease or those neurons do not constitutively express these kinases within degenerating neurons (Mailliot C et al, 1998).…”

La maladie d’Alzheimer : une tauopathie parmi d’autres ?

“…Ces neurones ne contiennent pas les isoformes 10+ de protéines tau [16]. Or, seules les isoformes de protéines tau hyperphosphorylées dépour-vues de la séquence codée par l'exon 10 (3R) présentent un tel profil électrophorétique [15,17]. Il est donc clair que des isoformes ne comportant pas cette séquence s'agrègent au sein des corps de Pick ( Figure 5).…”

“…Il est donc clair que des isoformes ne comportant pas cette séquence s'agrègent au sein des corps de Pick ( Figure 5). De plus, certains sites (KXGS), tels que les résidus Ser262 et 356, ne sont pas phosphorylés, suggérant l'absence ou l'inactivation des kinases impliquées dans cette phosphorylation, ou encore un problème d'accessibilité à ces sites [15,16]. Le profil électrophorétique des protéines tau permet donc de différencier certaines maladies neurodégéné-ratives.…”